TW202136266A - Sos1 inhibitors - Google Patents

Abstract

The present invention relates to compounds that inhibit Son of sevenless homolog 1 (SOS1) activity. In particular, the present invention relates to compounds, pharmaceutical compositions and methods of use, such as methods of treating cancer using the compounds and pharmaceutical compositions of the present invention.

Description

SOS1 inhibitor

The present invention relates to compounds that inhibit GTP-mediated nucleotide exchange of Son of sevenless homolog 1 (SOS1). In particular, the present invention relates to compounds, pharmaceutical compositions containing these compounds, and methods of use thereof.

The Ras family includes v-Ki-ras2 Kirsten rat sarcoma virus oncogene homolog ( KRAS ), neuroblastoma RAS virus oncogene homolog ( NRAS ), and Harvey mouse sarcoma virus oncogene ( HRAS ). Strictly regulate cell division, growth and function under the altered state of cancer (see, for example, Simanshu et al., "Cell", 2017. 170(1): pages 17-33; Matikas et al., "Oncology/Hematology" Review (Crit Rev Oncol Hematol)", 2017. 110: Pages 1-12). The RAS protein is activated by upstream signals including receptor tyrosine kinase (RTK), and signals several downstream signal pathways, such as the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathway. Due to mutations or changes in the RAS gene or other genes in the RAS pathway, excessive activation of the RAS signal is often observed in cancer. The determination of strategies for predicting the inhibition of RAS and RAS signaling is useful for the treatment of cancer and RAS modulating disease states.

The RAS protein is guanosine triphosphatase (GTPase), which cycles between the inactive guanosine diphosphate (GDP) binding state and the active guanosine triphosphate (GTP) binding state. No seven son protein homolog 1 (SOS1) is a guanine nucleotide exchange factor (GEF), which mediates GDP exchange GTP, thereby activating the RAS protein. RAS proteolytically hydrolyzes GTP into GDP through its inherent GTPase activity, which is greatly enhanced by GTP activated protein (GAP). This regulation via GAP and GEF is a mechanism that tightly regulates activation and inactivation under normal conditions. Mutations at several residues in all three RAS proteins are frequently observed in cancer and cause RAS to remain mainly in an activated state (Sanchez-Vega et al., "Cell", 2018. 173: pp. 321-337; Li et al. Human, "Nature Reviews Cancer (Nature Reviews Cancer)", 2018. 18: p.767-777). The mutations at codons 12 and 13 are the most frequently mutated RAS residues, and prevent GAP-stimulated GTP hydrolysis by blocking the interaction between GAP protein and RAS. However, recent biochemical analyses have confirmed that these mutant proteins still require an activated nucleotide cycle based on their intrinsic GTPases and/or partial sensitivity to exogenous GTPases. Therefore, mutant RAS proteins are sensitive to inhibiting upstream factors such as SOS1 or SHP2, which is another upstream signaling molecule required for RAS activation (Hillig, 2019; Patricelli, 2016; Lito, 2016; Nichols, 2018).

The three main RAS-GEF families that have been identified in mammalian cells are SOS, RAS-GRF and RAS-GRP (Rojas, 2011). RAS-GRF and RAS-GRP are expressed in central nervous system cells and hematopoietic cells, respectively, while the SOS family is widely expressed and is responsible for transducing RTK signaling. The SOS family includes SOS1 and SOS2 and these proteins have approximately 70% sequence identity. Due to the rapid degradation of SOS2, SOS1 seems to be more active than SOS2. Mouse SOS2 gene knockout is feasible, while SOS1 gene knockout is embryonic lethal. The SOS1 gene knockout mouse model induced by tamoxifen was used to inquire about the effects of SOS1 and SOS2 in adult mice and proved that SOS1 gene knockout is feasible, but SOS1/2 double gene knockout is not feasible (Baltanas , 2013), which shows that the function is redundant and the selective inhibition of SOS1 can have a sufficient therapeutic index for the treatment of SOS1-RAS activation diseases.

SOS protein is recruited into phosphorylated RTK via interaction with growth factor receptor binding protein 2 (GRB2). The recruitment of the plasma membrane brings SOS close to RAS and activates SOS-mediated RAS. The SOS protein binds to the RAS via a binding site that promotes nucleotide exchange and an ectopic site that binds to GTP-binding RAS family proteins and increases the function of SOS (Freedman et al., "Proc. Natl. Acad.Sci, USA)", 2006. 103(45): Pages 16692-97). Binding to ectopic sites reduces the steric hindrance of the RAS matrix binding site and is therefore necessary for nucleotide exchange. Due to the enhanced interaction of the key domains in the activated state, the retention of the active configuration at the catalytic site after interaction with the ectopic site is isolated. SOS1 mutations are present in Noonan syndrome and several cancers, including lung adenocarcinoma, embryonic rhabdomyosarcoma, Sertoli cell testicular tumors, and skin granulosa cell tumors (see, for example, Denayer, E. et al., Genes Chromosomes Cancer )", 2010. 49(3): Pages 242-52).

GTPase activating protein (GAP) is a protein that stimulates low endogenous GTPase activity of RAS family members, and therefore converts active GTP-bound RAS protein into inactive GDP-bound RAS protein (see, for example, Simanshu, DK, "Cell 》, 2017, Ras Proteins and their Regulators in Human Disease (Ras Proteins and their Regulators in Human Disease). When GEF SOS1 activation changes appear in cancer, GAP neurofibroma protein 1 (NF-1) or neurofibroma protein 2 (NF-2) inactivation mutations and dysfunctional changes also appear, resulting in inactivation of SOS1 Inhibited and increased downstream activity via the RAS protein pathway.

Therefore, the compounds of the present invention that block the interaction between SOS1 and members of the Ras family prevent the recycling of KRas into an active GTP-bound form, and thus can provide therapeutic benefits for various cancers, especially cancers related to members of the Ras family. The compounds of the present invention provide potential therapeutic benefits as inhibitors of the SOS1-KRas interaction, which can be used to block cancers in cells by treating various forms of cancer, including Ras-related cancers, SOS1-related cancers, and NF1/NF2-related cancers SOS1-KRas interact to negatively regulate KRas activity.

It is necessary to develop new SOS1 inhibitors, which can block the interaction between SOS1 and members of the Ras family, prevent KRas from recycling into an active GTP-bound form, and therefore may be a variety of cancers, especially including Ras-related cancers, SOS1-related cancers and NF1/NF2-related cancers provide therapeutic benefits.

式（I）In one aspect of the present invention, a compound represented by formula (I) is provided:

Formula (I)

Or a pharmaceutically acceptable salt thereof, in which:

R ¹ is hydrogen, hydroxyl, C1-C6 alkyl, alkoxy, -N(R ⁶ ) ₂ , -NR ⁶ C(O)R ⁶ , -C(O)N(R ⁶ ) ₂ , -SO ₂ Alkyl, -SO ₂ NR ⁶ alkyl, cycloalkyl, -Q-heterocyclyl, aryl or heteroaryl, wherein each of the cycloalkyl, heterocyclyl, aryl and heteroaryl groups is optionally connected to one Or multiple R ² or LR ² substitutions;

Each Q is independently a bond, O or NR ⁶ ;

X is N or CR ⁷ ;

Each R ^{2 is} independently C1-C3 alkyl, pendant oxy (ie, C=O), hydroxyl, halogen, cyano, hydroxyalkyl, haloalkyl, alkoxy, -C(O)N(R ⁶ ) ₂ , -N(R ⁶ ) ₂ , -SO ₂ alkyl, -NR ⁶ C(O)C1-C3 alkyl, -C(O)cycloalkyl, -C(O)C1-C3 alkyl , -C(O)heterocyclyl, aryl, heteroaryl or heterocyclyl, wherein the cycloalkyl, heterocyclyl, aryl, heteroaryl or heterocyclyl is each optionally through one or more R ¹¹ replace;

R ³ is hydrogen, C1-C6 alkyl, alkoxy, -N(R ¹⁰ ) ₂ , -LN(R ¹⁰ ) ₂ , cycloalkyl, haloalkyl or heterocyclic group, wherein the C1-C6 alkyl , Cycloalkyl and heterocyclyl are each ^{substituted with one or more R 9} as appropriate;

Y is a bond or heteroaryl group;

R ⁴ is an aryl group or a heteroaryl group, each of which is optionally substituted ^{with one or more R 5 groups;}

Each R ^{5 is} independently hydroxy, halogen, cyano, hydroxyalkyl, alkoxy, C1-C3 alkyl, haloalkyl, haloalkyl -OH, -N(R ⁶ ) ₂ , -LN(R ⁶ ) ₂ or -SO ₂ alkyl;

L is C1-C3 alkylene;

Each R ^{6 is} independently hydrogen, C1-C3 alkyl, haloalkyl or cycloalkyl;

R ⁷ is hydrogen, cyano or alkoxy;

R ⁸ is C1-C2 alkyl or halo C1-C2 alkyl;

Each R ^{9 is} independently hydroxyl, halogen, amino, cyano, alkoxy or C1-C3 alkyl;

Each R ^{10 is} independently hydrogen, C1-C3 alkyl or cycloalkyl;

Each R ^{11 is} independently C1-C3 alkyl, halogen or haloalkyl; and

R ¹² is hydrogen, halogen or C1-C3 alkyl.

In another aspect of the present invention, there is provided a pharmaceutical composition comprising a therapeutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

In another aspect, the present invention provides a method for inhibiting the activity of the Ras family member by inhibiting the association between the Ras family member and SOS1 in the cell, which comprises contacting the cell with a compound of formula (I). In one embodiment, the contact is ex vivo. In one embodiment, the contact is in vivo.

Also provided herein is a method for inhibiting cell proliferation in vitro or in vivo, the method comprising contacting cells with an effective amount of a compound of formula (I) as defined herein or a pharmaceutically acceptable salt or pharmaceutical composition thereof .

This article also provides a method for the treatment of cancer in an individual in need, the method comprising (a) determining that the cancer is related to mutations in Ras family members (for example, cancers related to KRas G12C) (for example, using a regulatory agency approved (For example, FDA approved) assay method or kit determination); and (b) administer a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or pharmaceutical composition thereof, to the patient.

This article also provides a method for the treatment of cancer in an individual in need, the method comprising (a) determining that the cancer is related to SOS1 mutations (such as SOS1 related cancers) (for example, if using a regulatory agency approved (such as FDA) Approved) determined by assay method or kit); and (b) administer a therapeutically effective amount of the compound of formula (I), or a pharmaceutically acceptable salt or pharmaceutical composition thereof, to the patient.

This article also provides a method for treating cancer in an individual in need, the method comprising (a) determining that the cancer is related to NF-1 or NF-2 loss-of-function mutations (e.g., NF1/NF2 related cancers) (e.g. , If determined using a test method or kit approved by a regulatory agency (such as FDA approved); and (b) administer a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or Pharmaceutical composition.

This document also provides a use of a compound of formula (I) as defined herein or a pharmaceutically acceptable salt or solvate thereof in the manufacture of a medicament for inhibiting the activity of SOS1.

This document also provides a use of a compound of formula (I) as defined herein or a pharmaceutically acceptable salt or solvate thereof in the manufacture of a medicament for the treatment of diseases or disorders related to SOS1.

The present invention relates to SOS1 inhibitors. Specifically, the present invention relates to a compound that inhibits the activity of SOS1, a pharmaceutical composition containing a therapeutically effective amount of the compound, and a method of use thereof. definition

Unless otherwise defined, all technical and scientific terms used herein have the same meanings as those commonly understood by those familiar with the present invention. All patents, patent applications and publications mentioned herein are incorporated by reference to the extent that they are consistent with the present invention. Unless explicitly defined otherwise, terms and ranges have their general defined definitions.

For the sake of simplicity, the chemical part is defined, and is mainly mentioned as a monovalent chemical part (such as alkyl, aryl, etc.) throughout the text. Nonetheless, these terms can also be used to convey the corresponding multivalent part under the appropriate structure that is clear to those familiar with the technology. For example, although the "alkyl" moiety generally refers to a monovalent group (such as CH ₃ -CH ₂ -), in some cases the divalent linking moiety can still be an "alkyl". In this case, familiarize yourself with this item The skilled person will understand the alkyl group as a divalent group (for example -CH ₂ -CH ₂ -), which is equivalent to the term "alkylene". (Similarly, in the case where a divalent moiety is required and it is stated as an "aryl group", those familiar with the art should understand that the term "aryl" refers to the corresponding divalent moiety, an aryl group). Understand that all atoms have their valences generally used for bond formation (ie, 4 for carbon, 3 for N, 2 for O, and depending on the oxidation state of S, 2, 4, or 6 for S) .

As used herein, "KRas G12C" refers to a mutant form of the mammalian KRas protein, which contains the amino acid substitution of cysteine to glycine at position 12 of the amino acid. The assignment of amino acid codons and residue positions of human KRas is based on the amino acid sequence identified by UniProtKB/Swiss-Prot P01116: variant p.Gly12Cys.

As used herein, "KRas G12D" refers to a mutant form of the mammalian KRas protein, which contains an amino acid substitution of aspartic acid to glycine at position 12 of the amino acid. The assignment of amino acid codons and residue positions of human KRas is based on the amino acid sequence identified by UniProtKB/Swiss-Prot P01116: variant p.Gly12Asp.

As used herein, "KRas G12S" refers to a mutant form of the mammalian KRas protein, which contains the amino acid substitution of serine to glycine at position 12 of the amino acid. The assignment of amino acid codons and residue positions of human KRas is based on the amino acid sequence identified by UniProtKB/Swiss-Prot P01116: variant p.Gly12Ser.

As used herein, "KRas G12A" refers to a mutant form of the mammalian KRas protein that contains alanine to glycine amino acid substitution at position 12 of the amino acid. The assignment of amino acid codons and residue positions of human KRas is based on the amino acid sequence identified by UniProtKB/Swiss-Prot P01116: variant p.Gly12Ala.

As used herein, "KRas G13D" refers to a mutant form of the mammalian KRas protein, which contains an amino acid substitution of aspartic acid to glycine at position 13 of the amino acid. The assignment of amino acid codons and residue positions of human KRas is based on the amino acid sequence identified by UniProtKB/Swiss-Prot P01116: variant p.Gly13Asp.

As used herein, "KRas G13C" refers to a mutant form of the mammalian KRas protein, which contains the amino acid substitution of cysteine to glycine at position 13 of the amino acid. The assignment of amino acid codons and residue positions of human KRas is based on the amino acid sequence identified by UniProtKB/Swiss-Prot P01116: variant p.Gly13Cys.

As used herein, "KRas Q61L" refers to a mutant form of mammalian KRas protein that contains an amino acid substitution of leucine to glutamic acid at position 41 of the amino acid. The assignment of amino acid codons and residue positions of human KRas is based on the amino acid sequence identified by UniProtKB/Swiss-Prot P01116: variant p.Gln61Leu.

As used herein, "KRas A146T" refers to a mutant form of the mammalian KRas protein that contains the amino acid substitution of threonine to alanine at position 146 of the amino acid. The assignment of amino acid codons and residue positions of human KRas is based on the amino acid sequence identified by UniProtKB/Swiss-Prot P01116: variant p.Ala146Thr.

As used herein, "KRas A146V" refers to a mutant form of the mammalian KRas protein, which contains the amino acid substitution of valine to alanine at position 146 of the amino acid. The assignment of amino acid codons and residue positions of human KRas is based on the amino acid sequence identified by UniProtKB/Swiss-Prot P01116: variant p.Ala146Val.

As used herein, "KRas A146P" refers to a mutant form of the mammalian KRas protein that contains the amino acid substitution of proline to alanine at position 146 of the amino acid. The assignment of amino acid codons and residue positions of human KRas is based on the amino acid sequence identified by UniProtKB/Swiss-Prot P01116: variant p.Ala146Pro.

As used herein, "HRas G12C" refers to a mutant form of the mammalian HRas protein, which contains the amino acid substitution of cysteine to glycine at position 12 of the amino acid. The assignment of amino acid codons and residue positions of human HRas is based on the amino acid sequence identified by UniProtKB/Swiss-Prot P01112: variant p.Gly12Cys.

As used herein, "HRas G12D" refers to a mutant form of the mammalian HRas protein, which contains an amino acid substitution of aspartic acid to glycine at position 12 of the amino acid. The assignment of amino acid codons and residue positions of human HRas is based on the amino acid sequence identified by UniProtKB/Swiss-Prot P01112: variant p.Gly12Asp.

As used herein, "HRas G12S" refers to a mutant form of the mammalian HRas protein, which contains the amino acid substitution of serine to glycine at position 12 of the amino acid. The assignment of amino acid codons and residue positions of human HRas is based on the amino acid sequence identified by UniProtKB/Swiss-Prot P01112: variant p.Gly12Ser.

As used herein, "HRas G12A" refers to a mutant form of mammalian HRas protein that contains the amino acid substitution of alanine to glycine at position 12 of the amino acid. The assignment of amino acid codons and residue positions of human KRas is based on the amino acid sequence identified by UniProtKB/Swiss-Prot P01112: variant p.Gly12Ala.

As used herein, "HRas G13D" refers to a mutant form of mammalian HRas protein, which contains an amino acid substitution of aspartic acid to glycine at position 13 of the amino acid. The assignment of amino acid codons and residue positions of human HRas is based on the amino acid sequence identified by UniProtKB/Swiss-Prot P01112: variant p.Gly13Asp.

As used herein, "HRas G13C" refers to a mutant form of the mammalian HRas protein, which contains the amino acid substitution of cysteine to glycine at position 13 of the amino acid. The assignment of amino acid codons and residue positions of human HRas is based on the amino acid sequence identified by UniProtKB/Swiss-Prot P01112: variant p.Gly13Cys.

As used herein, "HRas Q61L" refers to a mutant form of mammalian HRas protein, which contains an amino acid substitution of leucine to glutamic acid at amino acid position 41. The assignment of amino acid codons and residue positions of human HRas is based on the amino acid sequence identified by UniProtKB/Swiss-Prot P01112: variant p.Gln61Leu.

As used herein, "HRas A146T" refers to a mutant form of the mammalian HRas protein, which contains the amino acid substitution of threonine to alanine at position 146 of the amino acid. The assignment of amino acid codons and residue positions of human NRas is based on the amino acid sequence identified by UniProtKB/Swiss-Prot P01112: variant p.Ala146Thr.

As used herein, "Hras A146V" refers to a mutant form of the mammalian HRas protein, which contains the amino acid substitution of valine to alanine at position 146 of the amino acid. The assignment of amino acid codons and residue positions of human NRas is based on the amino acid sequence identified by UniProtKB/Swiss-Prot P01112: variant p.Ala146Val.

As used herein, "HRas A146P" refers to a mutant form of the mammalian HRas protein that contains the amino acid substitution of proline to alanine at position 146 of the amino acid. The assignment of amino acid codons and residue positions of human NRas is based on the amino acid sequence identified by UniProtKB/Swiss-Prot P01112: variant p.Ala146Pro.

As used herein, "NRas G12C" refers to a mutant form of the mammalian NRas protein, which contains the amino acid substitution of cysteine to glycine at position 12 of the amino acid. The assignment of amino acid codons and residue positions of human NRas is based on the amino acid sequence identified by UniProtKB/Swiss-Prot P01111: variant p.Gly12Cys.

As used herein, "NRas G12D" refers to a mutant form of mammalian NRas protein, which contains aspartic acid to amino acid instead of glycine at position 12 of the amino acid. The assignment of amino acid codons and residue positions of human NRas is based on the amino acid sequence identified by UniProtKB/Swiss-Prot P01111: variant p.Gly12Asp.

As used herein, "NRas G12S" refers to a mutant form of mammalian NRas protein that contains the amino acid substitution of serine to glycine at position 12 of the amino acid. The assignment of amino acid codons and residue positions of human NRas is based on the amino acid sequence identified by UniProtKB/Swiss-Prot P01111: variant p.Gly12Ser.

As used herein, "NRas G12A" refers to a mutant form of mammalian NRas protein that contains the amino acid substitution of alanine to glycine at position 12 of the amino acid. The assignment of amino acid codons and residue positions of human KRas is based on the amino acid sequence identified by UniProtKB/Swiss-Prot P01111: variant p.Gly12Ala.

As used herein, "NRas G13D" refers to a mutant form of mammalian NRas protein that contains an amino acid substitution of aspartic acid to glycine at position 13 of the amino acid. The assignment of amino acid codons and residue positions of human NRas is based on the amino acid sequence identified by UniProtKB/Swiss-Prot P01111: variant p.Gly13Asp.

As used herein, "HNRas G13C" refers to a mutant form of the mammalian NRas protein, which contains the amino acid substitution of cysteine to glycine at position 13 of the amino acid. The assignment of amino acid codons and residue positions of human NRas is based on the amino acid sequence identified by UniProtKB/Swiss-Prot P01111: variant p.Gly13Cys.

As used herein, "HRas Q61L" refers to a mutant form of mammalian HRas protein, which contains an amino acid substitution of leucine to glutamic acid at amino acid position 41. The assignment of amino acid codons and residue positions of human HRas is based on the amino acid sequence identified by UniProtKB/Swiss-Prot P01112: variant p.Gln61Leu.

As used herein, "Nras A146T" refers to a mutant form of the mammalian NRas protein, which contains the amino acid substitution of threonine to alanine at the amino acid position 146. The assignment of amino acid codons and residue positions of human NRas is based on the amino acid sequence identified by UniProtKB/Swiss-Prot P01111: variant p.Ala146Thr.

As used herein, "NRas A146V" refers to a mutant form of the mammalian NRas protein, which contains the amino acid substitution of valine to alanine at position 146 of the amino acid. The assignment of amino acid codons and residue positions of human NRas is based on the amino acid sequence identified by UniProtKB/Swiss-Prot P01111: variant p.Ala146Val.

As used herein, "NRas A146P" refers to a mutant form of the mammalian NRas protein, which contains the amino acid substitution of proline to alanine at position 146 of the amino acid. The assignment of amino acid codons and residue positions of human NRas is based on the amino acid sequence identified by UniProtKB/Swiss-Prot P01111: variant p.Ala146Pro.

As used herein, "Ras family member" or "Ras family" refers to KRas, HRas, NRas and their activating mutants, including positions G12, G13, Q61 and A146.

As used herein, "Ras family-related disease or disorder" refers to a disease or disorder related to, mediated by, or having an activated Ras mutation, such as a position of G12, G13, Q61 or A146. Non-limiting examples of diseases or disorders related to the Ras family are cancers related to KRas, HRas, or NRas G12C; cancers related to KRas, HRas, or Nras G12D; cancers related to KRas, HRas, or Nras G12S; cancers related to KRas, HRas, or Nras G12A Cancers related to KRas, HRas, or Nras G13D; Cancers related to KRas, HRas, or NRas G13C; Cancers related to KRas, HRas, or Nras Q61X; Cancers related to KRas, HRas, or Nras A146T; Cancers related to KRas, Hras, or Nras A146V Cancer or KRas, HRas, or NRas A146P related cancers.

As used herein, "SOS1" refers to the Mammal Non-Seven Child Protein Homolog 1 (SOS1) enzyme.

As used herein, "SOS1-related disease or disorder" refers to a disease or disorder that is related to, mediated by, or has an activating SOS1 mutation. Examples of activating SOS1 mutations include SOS1 N233S and SOS1 N233Y mutations.

As used herein, "SOS1 N233S" refers to a mutant form of the mammalian SOS1 protein, which contains the amino acid substitution of serine to glutamic acid at the amino acid position 233. The assignment of amino acid codons and residue positions of human SOS1 is based on the amino acid sequence identified by UniProtKB/Swiss-Prot Q07889: variant p.Gln233Ser.

As used herein, "SOS1 N233Y" refers to a mutant form of mammalian SOS1 protein that contains an amino acid substitution of tyrosine to glutamic acid at position 233 of the amino acid. The assignment of amino acid codons and residue positions of human SOS1 is based on the amino acid sequence identified by UniProtKB/Swiss-Prot Q07889: variant p.Gln233Tyr.

As used herein, "SOS1 inhibitor" refers to a compound of the present invention represented by formula (I) as described herein. These compounds can adversely inhibit all or part of the interaction between SOS1 and Ras family mutants or SOS1 activating mutations, thereby reducing and/or regulating the nucleotide exchange activity of the Ras family member-SOS1 complex.

As used herein, "NF-1/NF-2 related disease or disorder" refers to the loss of function mutation in the neurofibroma protein (NF-1) gene or neurofibroma protein 2 (NF-2) gene, or Diseases or disorders mediated or possessed by it.

As used herein, "loss-of-function mutation" refers to any point mutation, splice site mutation, fusion, nonsense mutation (amino acid mutation into a stop codon), same-frame or frame-shift mutation (including insertions and deletions) and coding The homozygous deletion of the gene of the protein in the target cell or cancer cell results in partial or complete loss of the existence, activity, and/or function of the encoded protein.

The term "amino" refers to -NH ₂ .

The term "acetyl" refers to "-C(O)CH ₃ ".

As used herein, the term "acyl" refers to an alkylcarbonyl or arylcarbonyl substituent, where the alkyl and aryl moieties are as defined herein.

The term "alkyl" as used herein refers to straight and branched chain aliphatic groups having 1 to 12 carbon atoms. Therefore, "alkyl" encompasses C ₁ , C ₂ , C ₃ , C ₄ , C ₅ , C ₆ , C ₇ , C ₈ , C ₉ , C ₁₀ , C ₁₁ and C ₁₂ groups. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, second butyl, tertiary butyl, pentyl, and hexyl.

The term "alkenyl" as used herein means an unsaturated straight or branched chain aliphatic group having one or more carbon-carbon double bonds and having 2 to 12 carbon atoms. Therefore, "alkenyl" encompasses C ₂ , C ₃ , C ₄ , C ₅ , C ₆ , C ₇ , C ₈ , C ₉ , C ₁₀ , C ₁₁ and C ₁₂ groups. Examples of alkenyl include, but are not limited to, ethenyl, propenyl, butenyl, pentenyl, and hexenyl.

The term "alkynyl" as used herein means an unsaturated straight-chain or branched-chain aliphatic group having one or more carbon-carbon bonds and having 2 to 12 carbon atoms. Therefore, "alkynyl" encompasses C ₂ , C ₃ , C ₄ , C ₅ , C ₆ , C ₇ , C ₈ , C ₉ , C ₁₀ , C ₁₁ and C ₁₂ groups. Examples of alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, and hexynyl.

"Alkylene", "alkenylene" or "alkynylene" is an alkyl, alkenyl or alkynyl group as defined above, which is positioned between two other chemical groups and used to connect two other chemical groups Group. Examples of alkylene include, but are not limited to, methylene, ethylene, propylene, and butylene. Exemplary alkenylene groups include, but are not limited to, vinylene, propenylene, and butenylene. Exemplary alkynylene groups include, but are not limited to, ethynylene, propynylene, and butynylene.

The term "alkoxy" refers to -OC1-C6 alkyl.

The term "cycloalkyl" as used herein is a saturated and partially unsaturated cyclic hydrocarbon group having 3 to 12 carbons. Therefore, "cycloalkyl" includes C ₃ , C ₄ , C ₅ , C ₆ , C ₇ , C ₈ , C ₉ , C ₁₀ , C ₁₁ and C ₁₂ cyclic hydrocarbon groups. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl.

The term "heteroalkyl" refers to an alkyl group as defined above, wherein one or more carbon atoms in the chain are independently replaced by O, S, or NR ^x , where R ^x is hydrogen or C1-C3 alkyl. Examples of heteroalkyl groups include methoxymethyl, methoxyethyl, and methoxypropyl.

"Aryl" is a C ₆ -C ₁₄ aromatic moiety containing one to three aromatic rings. Therefore, "aryl" includes C ₆ , C ₁₀ , C ₁₃ and C ₁₄ cyclic hydrocarbon groups. An exemplary aryl group is a C ₆ -C ₁₀ aryl group. Specific aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, and stilbene. "Aryl" also includes fused polycyclic (for example, bicyclic) ring systems, in which one or more of the fused rings are non-aromatic, and the restriction is that at least one ring is aromatic, such as indenyl.

"Aralkyl" or "arylalkyl" includes an aryl group covalently attached to an alkyl group, where the moiety is attached to another group via the alkyl moiety. Exemplary aralkyl groups are -(C1-C6)alkyl(C6-C10)aryl groups, including but not limited to benzyl, phenethyl, and naphthylmethyl.

基、咪唑啉基、噻唑啶基、硫雜環丁烷基、二硫雜環己烷基、三硫雜環己烷基、氮雜硫雜環己烷基、氧硫雜環己烷基、二氧雜環己烷基、

唑啶基、

唑啶酮基、十氫喹啉基、哌啶酮基、4-哌啶酮基、硫

啉基、二甲基-

啉基及

啉基。A "heterocyclyl" or "heterocyclic" group has 3 to 12 atoms (3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 atoms) or 3 to 12 atoms ( 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13 atoms), such as a monocyclic or bicyclic (fused, spiro or bridged) ring structure of 4 to 8 atoms, where One or more ring atoms are independently -C(O)-, N, NR ⁴ , O, S, or S(O) ₂ , and the remaining ring atoms are quaternary carbons or carbonyl carbons. Examples of heterocyclic groups include, but are not limited to, epoxy, oxiranyl, oxetanyl, azetidinyl, aziridinyl, tetrahydrofuranyl, tetrahydropiperanyl, tetrahydrothiophene Group, pyrrolidinyl, piperidinyl, piper

Group, imidazolinyl, thiazolidinyl, thietanyl, dithiacyclohexyl, trithiacyclohexyl, azathiacyclohexyl, oxathionyl, Dioxanyl,

Oxazolidinyl,

Azolidinone, decahydroquinolinyl, piperidinone, 4-piperidinone, sulfur

Linyl, dimethyl-

Linyl and

Linyl.

As used herein, "heterocyclic group" refers to a heterocyclic group covalently linked to another group via a bond.

As used herein, the term "heteroaryl" refers to having 5 to 14 ring atoms, preferably 5, 6, 10, 13 or 14 ring atoms; having 6, 10 or 14 π shared in a ring array For the group of electrons, the cyclic array may include 1, 2 or 3 rings, and in addition to carbon atoms, it has one to three heteroatoms each independently being N, O or S. "Heteroaryl" also includes fused polycyclic (such as bicyclic, tricyclic) ring systems, in which one or more fused rings are non-aromatic (no matter which ring is connected), and the restriction is that at least one ring is aromatic And at least one of the rings contains one N, O or S ring atom.

唑-2(3H)-酮、2H-苯并[b][1,4]

-3(4H)-酮、苯并硫呋喃基、苯并噻吩基、苯并

唑基、苯并噻唑基、苯并三唑基、苯并四唑基、苯并異

唑基、苯并異噻唑基、苯并咪唑啉基、咔唑基、4aH-咔唑基，咔啉基、口克烷基、口克烯基、

啉基、呋喃基、呋呫基、咪唑啉基、咪唑基、1H-吲唑基、吲哚烯基、吲哚啉基、吲哚

基、吲哚基、3H-吲哚基、異苯并呋喃基、異口克烷基、異吲唑基、異吲哚啉基、異吲哚基、異喹啉基、異噻唑基、異

唑基、

啶基、八氫異喹啉基、

二唑基、1,2,3-

二唑基、1,2,4-

二唑基、1,2,5-

二唑基、1,3,4-

二唑基、

唑啶基、

唑基、

唑啶基、嘧啶基、啡啶基、啡啉基、啡

基、啡噻

基、啡

噻基、啡

基、呔

基、向日葵基、喋啶基、嘌呤基、哌喃基、吡

基、吡唑啶基、吡唑啉基、吡唑基、嗒

基、吡啶并

唑基、吡啶并咪唑基、吡啶并噻唑基、吡啶基、吡啶基、嘧啶基、吡咯啉基、2H-吡咯基、吡咯基、喹唑啉基、喹啉基、4H-喹

基、喹

啉基、口昆啶基、四氫異喹啉基、四氫喹啉基、四唑基、6H-1,2,5-噻二

基、1,2,3-噻二唑基、1,2,4-噻二唑基、1,2,5-噻二唑基、1,3,4-噻二唑基、噻嗯基、噻唑基、噻吩基、噻吩并噻唑基、噻吩并

唑基、噻吩并咪唑基、噻吩基、三

基、1,2,3-三唑基、1,2,4-三唑基、1,2,5-三唑基、1,3,4-三唑基及

基。Examples of heteroaryl groups include acridinyl, azecinyl, benzimidazolyl, benzofuranyl, benzo[d]

Oxazole-2(3H)-one, 2H-benzo[b][1,4]

-3(4H)-ketone, benzothiofuranyl, benzothienyl, benzo

Azolyl, benzothiazolyl, benzotriazole, benzotetrazolyl, benziso

Azolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, crosalkyl, croskenyl,

Linyl, furanyl, furanyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indole

Group, indolyl, 3H-indolyl, isobenzofuranyl, iso-indolyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, iso

Azole,

Ridinyl, octahydroisoquinolinyl,

Diazolyl, 1,2,3-

Diazolyl, 1,2,4-

Diazolyl, 1,2,5-

Diazolyl, 1,3,4-

Diazolyl,

Oxazolidinyl,

Azole,

Azolyridinyl, pyrimidinyl, phenanthridinyl, phenanthrinyl, phenanthrene

Phenanthrene

Base, brown

Thioyl, phenanthrene

Ji, eh

Group, sunflower group, pteridine group, purinyl group, piperanyl group, pyridine group

Group, pyrazolidinyl, pyrazolinyl, pyrazolyl, and

Base, pyrido

Azolyl, pyridoimidazolyl, pyridothiazolyl, pyridyl, pyridyl, pyrimidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quino

Quinine

Linyl, quindinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, 6H-1,2,5-thiadi

Group, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thienyl, Thiazolyl, thienyl, thienothiazolyl, thieno

Azolyl, thienoimidazolyl, thienyl, three

Group, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl and

base.

啉基甲基及苯并噻吩基乙基。此術語之範疇特定地排除具有相鄰環O及/或S原子之化合物。"Heteroaralkyl" or "heteroarylalkyl" includes a heteroaryl group covalently linked to another group via a bond. Examples of heteroalkyl groups include C ₁ -C ₆ alkyl groups and heteroaryl groups having 5, 6, 9 or 10 ring atoms. Examples of heteroaralkyl include pyridyl methyl, pyridyl ethyl, pyrrolyl methyl, pyrrolyl ethyl, imidazolyl methyl, imidazolyl ethyl, thiazolyl methyl, thiazolyl ethyl, benzimidazole Methyl, benzimidazolyl ethyl, quinazolinyl methyl, quinolinyl methyl, quinolinyl ethyl, benzofuranyl methyl, indolinyl ethyl, isoquinolinyl methyl , Isoindolyl methyl,

Alkylmethyl and benzothienylethyl. The scope of this term specifically excludes compounds with adjacent ring O and/or S atoms.

"Arylene", "heteroaryl" or "heterocyclyl" are respectively a divalent aryl, heteroaryl or heterocyclic group as defined above, which is positioned between two other chemical groups and Used to connect two other chemical groups.

As used herein, when a moiety (e.g., cycloalkyl, aryl, heteroaryl, heterocyclic, urea, etc.) is described as "optionally substituted" without explicitly stating the substituent, it means the group It has one to four, preferably one to three, more preferably one or two non-hydrogen substituents as appropriate.

The term "halogen" or "halo" as used herein refers to chlorine, bromine, fluorine or iodine.

The term "haloalkyl" refers to an alkyl chain in which one or more hydrogens have been replaced by halogen. Exemplary haloalkyl groups are trifluoromethyl, difluoromethyl, fluorochloromethyl, chloromethyl, and fluoromethyl.

The term "hydroxyalkyl" refers to -alkylene-OH.

As used herein, the terms "subject", "individual" or "patient" are used interchangeably and refer to any animal, including mammals, such as mice, rats, other rodents, rabbits, and dogs. , Cats, pigs, cattle, sheep, horses, primates and humans. In some embodiments, the patient is a human. In some instances, the individual has experienced and/or exhibited at least one symptom of the disease or condition to be treated and/or prevented. In some embodiments, the individual has been identified or diagnosed as having cancer with a KRas G12 or G13 mutation (eg, as determined using a regulatory agency-approved (eg, FDA-approved) assay or kit). In some embodiments, the individual has a tumor that is positive for KRas G12C mutations, KRas G12D mutations, KRas G12S mutations, KRas G12A mutations, KRas G13D mutations, or KRas G13C mutations (e.g., as approved by a regulatory agency (e.g., FDA approved) The) verification method or kit determination). The individual may be an individual with a tumor that is positive for Kras G12C mutation, KRas G12D mutation, KRas G12S mutation, KRas G12A mutation, KRas G13D mutation, or KRas G13C mutation (for example, if using a test approved by a regulatory agency (for example, FDA approved) Method or kit identification is positive). The individual may have a KRas G12C mutation, KRas G12D mutation, KRas G12S mutation, KRas G12A mutation, KRas G13D mutation, or KRas G13C mutation in their tumors (for example, if using a regulatory agency approved (for example, FDA approved) assay or reagent Box to identify tumors). In some embodiments, it is suspected that the individual has KRas G12 or G13 gene-related cancer. In some embodiments, the individual's clinical records indicate that the individual has a tumor with a KRas G12C mutation (and optionally, the clinical records indicate that the individual is treated with any of the compositions provided herein).

As used herein, the term "pediatric patient" refers to a patient who is under 16 years of age at the time of diagnosis or treatment. The term "pediatrics" can be further divided into different subgroups, which include: newborns (from birth to the first month of life); infants (1 month to two years); children (two years to 12 years); and adolescents (12 To 21 years old (up to but not including the 22nd birthday)). Berhman RE, Kliegman R, Arvin AM, Nelson WE. "Nelson Textbook of Pediatrics", 15th edition. Philadelphia: WB Saunders Company (Philadelphia: WB Saunders Company), 1996; Rudolph AM and others , "Rudolph's Pediatrics", 21st edition. New York: McGraw-Hill (New York: McGraw-Hill), 2002; and Avery MD, First LR. "Pediatric Medicine (Pediatric Medicine) )", second edition. Baltimore: Williams & Wilkins Press (Baltimore: Williams &Wilkins); 1994.

As used herein, the "effective amount" of a compound is an amount sufficient to negatively regulate or inhibit the activity of the SOS1 enzyme.

As used herein, a "therapeutically effective amount" of a compound is an amount sufficient to ameliorate or reduce symptoms in some way or stop or reverse the progression of the condition, or negatively regulate or inhibit the activity of SOS1. This amount can be administered in a single dose or can be administered according to a schedule, whereby it is effective.

As used herein, "treatment" means any way to improve or otherwise beneficially alter the patient's condition, disorder, or symptoms or pathology of the disease.

As used herein, "ameliorating the symptoms of a specific condition by administering a specific compound or a pharmaceutical composition" refers to the administration of the composition or any alleviation associated with the administration of the composition, whether permanent or temporary Long-lasting or short-lived. Compound

式（I）In one aspect of the present invention, a compound represented by formula (I) is provided:

Formula (I)

Or its pharmaceutically acceptable salt,

in:

R ¹ is hydrogen, hydroxyl, C1-C6 alkyl, alkoxy, -N(R ⁶ ) ₂ , -NR ⁶ C(O)R ⁶ , -C(O)N(R ⁶ ) ₂ , -SO ₂ Alkyl, -SO ₂ NR ⁶ alkyl, cycloalkyl, -Q-heterocyclyl, aryl or heteroaryl, wherein each of the cycloalkyl, heterocyclyl, aryl and heteroaryl groups is optionally connected to one Or multiple R ² or LR ² substitutions;

Each Q is independently a bond, O or NR ⁶ ;

X is N or CR ⁷ ;

Each R ^{2 is} independently C1-C3 alkyl, pendant oxy (ie (C=O)), hydroxy, halogen, cyano, hydroxyalkyl, haloalkyl, alkoxy, -C(O)N( R ⁶ ) ₂ , -N(R ⁶ ) ₂ , -SO ₂ alkyl, -NR ⁶ C(O)C1-C3 alkyl, -C(O)cycloalkyl, -C(O)C1-C3 alkane Group, -C(O)heterocyclyl, aryl, heteroaryl or heterocyclyl, wherein the cycloalkyl, heterocyclyl, aryl, heteroaryl or heterocyclic group is each optionally through one or more R ¹¹ replaced;

R ³ is hydrogen, C1-C6 alkyl, alkoxy, -N(R ¹⁰ ) ₂ , -LN(R ¹⁰ ) ₂ , cycloalkyl, haloalkyl or heterocyclic group, wherein the C1-C6 alkyl , Cycloalkyl and heterocyclyl are each ^{substituted with one or more R 9} as appropriate;

Y is a bond or heteroaryl group;

R ⁴ is an aryl group or a heteroaryl group, each of which is optionally substituted ^{with one or more R 5 groups;}

Each R ^{5 is} independently hydroxy, halogen, cyano, hydroxyalkyl, alkoxy, C1-C3 alkyl, haloalkyl, haloalkyl -OH, -N(R ⁶ ) ₂ , -LN(R ⁶ ) ₂ or -SO ₂ alkyl;

L is C1-C3 alkylene;

Each R ^{6 is} independently hydrogen, C1-C3 alkyl, haloalkyl or cycloalkyl;

R ⁷ is hydrogen, cyano or alkoxy;

R ⁸ is C1-C2 alkyl or halo C1-C2 alkyl;

Each R ^{9 is} independently hydroxyl, halogen, amino, cyano, alkoxy or C1-C3 alkyl;

Each R ^{10 is} independently hydrogen, C1-C3 alkyl or cycloalkyl;

Each R ^{11 is} independently C1-C3 alkyl, halogen or haloalkyl; and

R ¹² is hydrogen, halogen or C1-C3 alkyl.

In one embodiment of the compound of formula (I), X is N. In certain embodiments where X is N, R ¹ is alkoxy. In one embodiment, the alkoxy group is methoxy.

啉基、哌

基或哌

酮。在某些實施例中，雜環基為

啉基或哌

基，Y為鍵，且R⁴ 為視情況經一個或多個R⁵ 取代之芳基。在一個實施例中，雜環基為

啉基、哌

基或哌

酮，Y為伸雜芳基，且R⁴ 為視情況經一個或多個R⁵ 取代之芳基。In one embodiment of the compound of formula (I), X is N. In certain embodiments where X is N, R ¹ is -Q-heterocyclyl optionally substituted with one or more R ^2. In certain embodiments, R ¹ is -Q-heterocyclyl, and wherein Q is a bond, and the heterocyclyl is optionally substituted ^{with one or more R 2}

Linyl, Piper

Piperidine

ketone. In certain embodiments, the heterocyclic group is

Linyl or Piper

Group, Y is a bond, and R ⁴ is an aryl group substituted with one or more R ^{5 as appropriate.} In one embodiment, the heterocyclic group is

Linyl, Piper

Piperidine

In the ketone, Y is a heteroaryl group, and R ⁴ is an aryl group substituted with one or more R ^{5 as appropriate.}

啉基、橋聯哌

基或橋聯哌

酮。In certain embodiments of the present invention, R ¹ is -Q-heterocyclyl, and wherein the heterocyclyl is bridged

Linyl, bridged piperazine

Bridged piperazine

ketone.

In certain embodiments of the present invention, R ¹ is -Q-heterocyclyl, and wherein the heterocyclyl is a spiro ring system containing two or more rings. In certain such embodiments, the spiro ring system comprises two rings each containing a heteroatom. In certain other such embodiments, the spiro ring system contains rings that do not have heteroatoms (ie, one ring has a heteroatom and one ring does not have a heteroatom).

基、5,6,7,8-四氫咪唑并吡

基、2,4,5,6-四氫吡咯并吡唑基、1,2,3,4-四氫苯并[4,5]咪唑并吡

基或4,5,6,7-四氫吡唑并吡

基。In certain embodiments of the present invention, R ¹ is heteroaryl, wherein the heterocyclic group is optionally substituted with one or more R ² or LR ² . In some of these embodiments, the heteroaryl group is a bicyclic or tricyclic ring system, which in addition to one or more aromatic rings also includes non-aromatic rings, for example bicyclic or tricyclic ring systems such as 5,6,7,8- Tetrahydro-[1,2,4]triazolopyridine

Base, 5,6,7,8-tetrahydroimidazopyridine

Group, 2,4,5,6-tetrahydropyrrolopyrazolyl, 1,2,3,4-tetrahydrobenzo[4,5]imidazopyrazole

Or 4,5,6,7-tetrahydropyrazolopyridine

base.

In one embodiment of the compound of formula (I), X is CR ⁷ . In one embodiment, when X is CR ⁷ , R ⁷ is cyano.

In one embodiment of the compound of formula (I), X is CR ⁷ . In one embodiment, when X is CR ⁷ , R ⁷ is hydrogen.

In one embodiment of the compound of formula (I), X is CR ⁷ , R ⁷ is hydrogen, and R ¹ is hydrogen. In another embodiment, R ¹ is hydroxyl. In certain embodiments, R ¹ is -N(R ⁶ ) ₂ . In one embodiment, wherein R ¹ is -N(R ⁶ ) ₂ and each R ⁶ is a C1-C3 alkyl group. In one embodiment, each C1-C3 alkyl group is a methyl group. In other embodiments, R ¹ is -NR ⁶ C(O)R ⁶ . In one embodiment, each C1-C3 alkyl group is a methyl group. In one embodiment, NR R ⁶ is hydrogen and the ⁶ C (O) R R ^{6 6} of a C1-3 alkyl group.

In another embodiment, when X is CR ⁷ and R ⁷ is hydrogen, R ¹ is -C(O)N(R ⁶ ) ₂ . In one embodiment, each C1-C3 alkyl group is a methyl group. In one embodiment, each C1-C3 alkyl group is hydrogen. In certain embodiments, R ¹ is -SO ₂ alkyl or -SO ₂ NR ⁶ alkyl. In one embodiment, R1 is -SO ₂ NR ⁶ alkyl, and R ⁶ is hydrogen. In other embodiments, R ¹ is a cycloalkyl substituted with one or more R ^{2 as appropriate.} In one embodiment, the cycloalkyl group is cyclobutyl, cyclopentyl, or cyclohexyl, each of which is optionally substituted ^{with one or more R 2.} In one embodiment, cyclobutyl, cyclopentyl or cyclohexyl is substituted with one R ² , where R ² is C1-C3 alkyl, alkoxy, hydroxy, or -N(R ⁶ ) ₂ . In one embodiment, R ² is -N(R ⁶ ) ₂ , and each R ⁶ is a C1-C3 alkyl group. In one embodiment, each C1-C3 alkyl group is a methyl group.

啉基、哌啶基、哌

基、N-甲基哌

基、哌

酮、1-甲基-哌

-2-酮、二氮雜環庚烷基、6,6-二氟-1,4-二氮雜環庚烷-1-基或4-甲基硫

啉1,1-二氧化物。在另一實施例中，Q為鍵，且雜環基為吡咯啶基或四氫哌喃基，其各自視情況經一個或多個R² 取代。在一個實施例中，吡咯啶基或四氫哌喃基經一個R² 取代，其中R² 為C1-C3烷基、烷氧基、羥基或-N(R⁶ )₂ 。In another embodiment, when X is CR ⁷ and R ⁷ is hydrogen, R ¹ is -Q-heterocyclyl optionally substituted with one or more R ^2. In one embodiment, Q is a bond, and the heterocyclic group is

Linyl, piperidinyl, piperidine

Base, N-methylpiper

Piperidine

Ketone, 1-methyl-piperidine

-2-one, diazepanyl, 6,6-difluoro-1,4-diazepan-1-yl or 4-methylsulfide

1,1-dioxide. In another embodiment, Q is a bond, and the heterocyclic group is pyrrolidinyl or tetrahydropiperanyl, each of which is optionally substituted ^{with one or more R 2.} In one embodiment, the pyrrolidinyl or tetrahydropiperanyl group is substituted with one R ² , wherein R ² is C1-C3 alkyl, alkoxy, hydroxy, or -N(R ⁶ ) ₂ .

基，其中R² 為視情況經一個或多個R¹¹ 取代之雜芳基。在一個實施例中，雜芳基為經兩個R¹¹ 取代之吡唑基，其中各R¹¹ 為C1-C3烷基。In another embodiment, when X is CR ⁷ and R ⁷ is hydrogen, R ¹ is -Q-heterocyclyl, Q is a bond and the heterocyclyl is piperyl substituted ^{with one R 2}

Group, wherein R ² is a heteroaryl group optionally substituted with one or more R ^11. In one embodiment, the heteroaryl group is a ^{pyrazolyl substituted with two R 11} , where each R ¹¹ is a C1-C3 alkyl group.

基，其中R² 為-C(O)環烷基或-C(O)雜環基，其中-C(O)環烷基或-C(O)雜環基之環烷基或雜環基部分各自視情況經一個或多個R¹¹ 取代。在一個實施例中，R² 為-C(O)環烷基，且環烷基為經一個R¹¹ 取代之環丙基，其中R¹¹ 為C1-C3烷基或鹵烷基。在一個實施例中，R² 為-C(O)雜環基，其中雜環基為氧雜環丁烷基、四氫呋喃基或四氫哌喃基。In another embodiment, when X is CR ⁷ and R ⁷ is hydrogen, R ¹ is -Q-heterocyclyl, Q is a bond and the heterocyclyl is piperyl substituted ^{with one R 2}

Group, where R ² is -C(O)cycloalkyl or -C(O)heterocyclyl, where -C(O)cycloalkyl or -C(O)heterocyclyl is cycloalkyl or heterocyclyl Each part is substituted with one or more R ¹¹ as appropriate. In one embodiment, R ² is -C(O)cycloalkyl, and cycloalkyl is ^{cyclopropyl substituted with one R 11} , wherein R ¹¹ is C1-C3 alkyl or haloalkyl. In one embodiment, R ² is -C(O) heterocyclyl, wherein the heterocyclyl is oxetanyl, tetrahydrofuranyl, or tetrahydropiperanyl.

-5(4H)-基、5,6-二氫咪唑并[1,5-a]吡

-7(8H)-基、1,3-二甲基-5,6-二氫咪唑并[1,5-a]吡

-7(8H)-基或(R)-2-甲基六氫吡咯并[1,2-a]吡

-6(2H)-酮。In one embodiment, Q is a bond, and the heterocyclic group is a bicyclic heterocyclic group. In certain embodiments, the bicyclic heterocyclyl is diazabicyclo[3.2.0]heptan-2-yl, (1R,5R)-2,6-diazabicyclo[3.2.0]hept-2-yl Diazabicyclo[3.2.0]heptan-6-yl, (1R,5R)-2,6-diazabicyclo[3.2.0]hept-6-yl, 6,7-dihydropyrazole And [1,5-a]pyridine

-5(4H)-base, 5,6-dihydroimidazo[1,5-a]pyridine

-7(8H)-yl, 1,3-dimethyl-5,6-dihydroimidazo[1,5-a]pyridine

-7(8H)-yl or (R)-2-methylhexahydropyrrolo[1,2-a]pyridine

-6(2H)-ketone.

In another embodiment, Q is O and the heterocyclyl is azetidinyl, tetrahydrofuranyl, pyrrolidinyl, or piperidinyl.

In another embodiment, when X is CR ⁷ and R ⁷ is hydrogen, R ¹ is an aryl group optionally substituted with one or more R ^2. In one embodiment, the aryl group is a phenyl ^{group optionally substituted with one or more R 2.} In certain embodiments, a phenyl group substituted with one R ^2, wherein R ² is C1-C3 alkyl, alkoxy, hydroxy, or -N (R ⁶⁾ _2. In one embodiment, R ² is -N(R ⁶ ) ₂ , and each R ⁶ is a C1-C3 alkyl group. In one embodiment, each C1-C3 alkyl group is a methyl group. In other embodiments, R ¹ is a heteroaryl substituted with one or more R ^{2 as appropriate.} In one embodiment, the heteroaryl group is a pyrazolyl group ^{optionally substituted with one or more R 2.} In one embodiment, the pyrazolyl is substituted with one R ² , where R ² is C1-C3 alkyl, alkoxy, hydroxy, or -N(R ⁶ ) ₂ . In one embodiment, R ² is -N(R ⁶ ) ₂ , and each R ⁶ is a C1-C3 alkyl group. In one embodiment, each C1-C3 alkyl group is a methyl group.

In one embodiment of the compound of formula (I), X is CR ⁷ and R ⁷ is alkoxy. In one embodiment, the alkoxy group is methoxy. In certain embodiments where X is CR ⁷ and R ⁷ is alkoxy, R ¹ is alkoxy. In one embodiment, R ⁷ alkoxy is methoxy and R ¹ alkoxy is methoxy.

In which formula X is N or CR certain embodiments of compounds of formula (I) of ^7, Y is a heteroaryl extension. In one embodiment, the heteroaryl group is thienyl.

In certain embodiments of the compound of formula (I) where X is N or CR ^{7, Y is a bond.}

In certain embodiments of compounds of formula (I), R ⁴ is aryl or heteroaryl, and each is optionally substituted ^{with one or more R 5.} In one embodiment, R ⁴ is an aryl group optionally substituted with one or more R ^5. In one embodiment, the aryl group is optionally substituted with one or more R ⁵ of the phenyl. In certain embodiments, a phenyl group substituted with one R ^5, wherein R ⁵ is C1-C4 alkyl, haloalkyl or -LN (R ⁶⁾ _2.

In one embodiment, R ⁵ is -LN(R ⁶ ) ₂ , where L is methylene, and one R ⁶ is hydrogen and the second R ⁶ is C1-C3 alkyl. In one embodiment, the C1-C3 alkyl group is methyl. In another embodiment, R ⁵ is -LN(R ⁶ ) ₂ , where L is methylene and each R ⁶ is C1-C3 alkyl. In one embodiment, each of the C1-C3 alkyl groups is a methyl group.

In certain embodiments where R ⁴ is aryl, R ⁴ is phenyl substituted with two R ⁵ , where one R ⁵ is C1-C4 alkyl and the second R ⁵ is haloalkyl. In one embodiment, the C1-C4 alkyl group is methyl and the haloalkyl group is trifluoromethyl. In certain embodiments, R ⁴ is a phenyl substituted with two R ⁵ , where one R ⁵ is C1-C4 alkyl and the second R ⁵ is -LN(R ⁶ ) ₂ . In one embodiment, L is methylene and each R ⁶ is C1-C3 alkyl.

In one embodiment of the compound of formula (I), R ³ is hydrogen.

In certain embodiments of the compound of formula (I), R ³ is a C1-C6 alkyl optionally substituted with one or more R ^9. In one embodiment, the C1-C6 alkyl group is methyl, ethyl or isopropyl.

In certain embodiments of compounds of formula (I), R ³ is alkoxy. In one embodiment, the alkoxy group is methoxy.

In certain embodiments of compounds of formula (I), R ³ is haloalkyl. In one embodiment, the haloalkyl group is trifluoromethyl.

In certain embodiments of the compound of formula (I), R ³ is a cycloalkyl optionally substituted with one or more R ^9. In one embodiment, the cycloalkyl group is cyclopropyl. In one embodiment, a cycloalkyl group substituted with one R ^9, wherein R ⁹ is a halo group, a hydroxyl group or an alkoxy group.

In certain embodiments of the compound of formula (I), R ³ is -N(R ¹⁰ ) ₂ . In one embodiment, each R ¹⁰ is a C1-C3 alkyl group. In certain embodiments, each C1-C3 alkyl group is methyl.

In certain embodiments of the compound of formula (I), R ³ is -LN(R ¹⁰ ) ₂ . In one embodiment, each R ¹⁰ is a C1-C3 alkyl group. In certain embodiments, each C1-C3 alkyl group is methyl.

In certain embodiments of the compound of formula (I), R ³ is a heterocyclic group, an aryl group or a heteroaryl group, wherein each of the heterocyclic group, aryl group and heteroaryl group is optionally substituted ^{with one or more R 9 groups} .

In certain embodiments of the compound of formula (I), R ⁸ is C1-C2 alkyl. In one embodiment, the C1-C2 alkyl group is methyl.

In certain embodiments of compounds of formula (I), R ⁸ is halo C1-C2 alkyl. In one embodiment, the halo C1-C2 alkyl group is fluoromethyl, difluoromethyl or trifluoromethyl.

, 及前述化合物之醫藥學上可接受之鹽。In one embodiment, the compound of formula (I) is:

, And pharmaceutically acceptable salts of the aforementioned compounds.

The compound of formula (I) can be formulated into a pharmaceutical composition. Pharmaceutical composition

In another aspect, the present invention provides a pharmaceutical composition comprising the SOS1 inhibitor according to the present invention and a pharmaceutically acceptable carrier, excipient or diluent. The compound of the present invention can be formulated by any method well known in the art, and can be prepared for administration by any route, including but not limited to parenteral, oral, sublingual, transdermal, topical, nasal Inside, trachea or rectum. In certain embodiments, the compound of the invention is administered intravenously in a hospital setting. In certain other embodiments, it may be better to administer by oral route.

The characteristics of the carrier will depend on the route of administration. As used herein, the term "pharmaceutically acceptable" means a non-toxic substance that is compatible with biological systems, such as cells, cell cultures, tissues, or biologics, and does not interfere with the effectiveness of the biological activity of the active ingredient. Therefore, in addition to inhibitors, the composition according to the present invention may contain diluents, fillers, salts, buffers, stabilizers, solubilizers and other materials well known in the art. The preparation of pharmaceutically acceptable formulations is described in, for example, Remington's Pharmaceutical Sciences, 18th edition, edited. A. Gennaro, Mack Publishing Co., Easton, Pennsylvania , Mid 1990.

As used herein, the term "pharmaceutically acceptable salt" refers to a salt that retains the desired biological activity of the above-identified compound and exhibits minimal or undesirable toxicological effects. Examples of such salts include, but are not limited to, acid addition salts formed from inorganic acids (such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, etc.), as well as those formed from acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, ascorbic acid, etc. , Benzoic acid, Tannic acid, Pamoic acid, Alginic acid, Polyglutamic acid, Naphthalenesulfonic acid, Naphthalenedisulfonic acid and polygalacturonic acid and other organic acid salts. The compounds can also be administered in the form of pharmaceutically acceptable quaternary salts known to those skilled in the art. Such quaternary salts specifically include quaternary ammonium salts of the formula -NR+Z-, where R is hydrogen, alkyl Or benzyl, and Z is a counter ion, including chloride, bromide, iodide, -O-alkyl, tosylate, methanesulfonate, sulfonate, phosphate or carboxylate (such as benzoate, Succinate, acetate, glycolate, maleate, malate, citrate, tartrate, ascorbate, benzoate, cinnamate, mandelate, benzyloxylate and diphenylacetate).

The active compound is included in a pharmaceutically acceptable carrier or diluent in an amount sufficient to deliver a therapeutically effective amount to the patient without causing serious toxicity to the treated patient. For all the conditions mentioned above, the dosage range of the active compound is about 0.01 to 300 mg/kg per day, preferably 0.1 to 100 mg/kg per day, and more generally 0.5 to about 25 mg per kilogram of recipient body weight per day. In a suitable carrier, a typical topical dosage range is 0.01-3% wt/wt. The effective dose range of the pharmaceutically acceptable derivative can be calculated based on the weight of the parent compound to be delivered. If the derivative itself exhibits activity, the effective dose can be estimated as described above using the weight of the derivative or by other methods known to those skilled in the art.

Pharmaceutical compositions containing the compounds of the invention can be used in the methods described herein. Instructions

In another aspect, the present invention provides a method for inhibiting SOS1 activity in cells, which comprises cells that need to inhibit SOS1 activity and an effective amount of a compound of formula (I), its pharmaceutically acceptable salt or containing the compound Or the pharmaceutical composition of its pharmaceutically acceptable salt is contacted in vitro.

In particular, it is believed that the compositions and methods provided herein can be used to inhibit SOS1 activity in cells. In one embodiment, the cells in which the activity of SOS1 needs to be inhibited are contacted with a therapeutically effective amount of the compound of formula (I) in vivo to negatively regulate the activity of SOS1. In other embodiments, a therapeutically effective amount of a pharmaceutically acceptable salt or a pharmaceutical composition containing the compound of formula (I) can be used. In one embodiment, the cell has an activating mutation of a member of the Ras family such as KRas, HRas, or NRas. In one embodiment, the cell has abnormal SOS1 activity. In one embodiment, the abnormal SOS1 activity is the result of an activating mutation of SOS1. In one embodiment, the SOS1 activating mutation is a N233S or N233Y mutation. In one embodiment, the cell has abnormal NF-1 or NF-2 activity. In one embodiment, the abnormal NF-1 or NF-2 activity is the result of an activating mutation of NF-1 or NF-2.

By negatively regulating the activity of SOS1, these methods are designed to block the interaction between SOS1 and members of the Ras family, and increase the GTP load of the RAS protein, thereby reducing or inhibiting the exchange of GTP nucleotides and removing the members of the Ras family. It is locked in the GDP binding zone in an inactive form, which leads to the inhibition of downstream Ras-mediated signal transduction. The cells can be contacted with a single dose or multiple doses according to a specific treatment plan to affect the required negative regulation of SOS1.

In another aspect, a method for treating cancer is provided, which comprises administering to a patient suffering from cancer a therapeutically effective amount of a compound of formula (I), a pharmaceutically acceptable salt thereof, or the compound or a pharmaceutically acceptable salt thereof. Pharmaceutical compositions of acceptable salts. In one embodiment, the cancer is a cancer related to the Ras family. In one embodiment, the cancer is SOS-1 related cancer. In one embodiment, the cancer is NF-1/NF-2 related cancer.

The compositions and methods provided herein can be used to treat a variety of cancers, including tumors such as prostate cancer, breast cancer, brain cancer, skin cancer, cervical cancer, and testicular cancer. More specifically, cancers that can be treated by the composition and method of the present invention include, but are not limited to, the following tumor types, such as astrocytic cancer, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, and esophageal cancer , Stomach cancer, head and neck cancer, hepatocellular carcinoma, laryngeal cancer, lung cancer, oral cancer, ovarian cancer, prostate cancer, thyroid cancer and sarcoma. More specifically, these compounds can be used to treat: heart: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyomas, fibroids, lipomas and teratomas; lung: bronchial carcinoma ( Squamous cells, undifferentiated small cells, undifferentiated large cells, adenocarcinoma), alveolar (bronchial) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondrogenic hamartoma, mesothelioma; gastrointestinal: esophagus ( Squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid, Vasoactive intestinal peptide tumor (vipoma), small intestine (adenocarcinoma, lymphoma, carcinoid, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large intestine (Adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); urogenital tract: kidney (adenocarcinoma, Wilm's tumor (Wilm's tumor), lymphoma, Leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (spermatoma, teratoma, embryonic carcinoma, teratoma, choriocarcinoma) , Sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenomatous tumor, lipoma); liver: liver cancer (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, blood vessel Tumors; biliary tract: gallbladder cancer, ampullary cancer, cholangiocarcinoma; bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (Reticular cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochondroma (osteochondral exostosis), benign chondroma, chondroblastoma, chondromycinoma, osteoid osteoma and Giant cell tumor; nervous system: skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges (meningioma, meningiosarcoma, glioma), brain (astrocytoma, medulla Cell tumor, glioma, ependymoma, blastoma (pineal tumor), glioblastoma multiforme, oligodendritic glioma, schwannoma, retinoblastoma, congenital Tumor), spinal cord (neurofibromas, meningioma, glioma, sarcoma); Gynecology: uterus (endometrial cancer), cervix (cervical cancer, precancerous cervical dysplasia), ovary (ovarian cancer (serous) Cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa-sheath cell tumor, Sertoli-Leydig cell tumor, dysgerminoma, malignant teratoma) , Vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonic rhabdomyosarcoma), fallopian tube (carcinoma); hematology : Blood (myelogenous leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphoid Cellular leukemia, myeloproliferative disease, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma); skin: malignant melanin Tumors, basal cell carcinoma, squamous cell carcinoma, Kaposi’s sarcoma, nevus dysplasia, lipoma, hemangioma, dermatofibroma, keloid, psoriasis; and adrenal gland: neuroblastoma. In certain embodiments, the cancer is diffuse large B-cell lymphoma (DLBCL).

In one embodiment, the cancer is a cancer related to the Ras family, such as a cancer related to Kras, NRas, or HRas. In certain embodiments, the cancer associated with the Ras family is non-small cell lung cancer or pancreatic cancer. In one embodiment, the cancer is SOS1-related cancer. In certain embodiments, SOS1-related cancers are lung adenocarcinoma, embryonal rhabdomyosarcoma, Sertoli cell testicular tumor, and skin granulosa cell tumor. In one embodiment, the cancer is an NF-1 related cancer.

The concentration and route of administration to the patient will vary depending on the cancer being treated. The compounds, their pharmaceutically acceptable salts, and pharmaceutical compositions containing such compounds and salts can also be co-administered with other anti-tumor compounds such as chemotherapy, or with radiological or surgical interventions, such as preoperative or surgical interventions. Later, adjuvants and other treatment methods are used in combination.General reaction process, intermediates and examples General reaction process

The compounds of the present invention can be prepared by using commercially available reagents and intermediates in the synthetic methods and reaction schemes described herein, or can be prepared by using other reagents and known methods familiar to those skilled in the art.

For example, the intermediates used to prepare the compound of the present invention and the compound of formula (I) can be prepared according to the general reaction scheme I-VI: General reaction scheme I

For general reaction scheme I, compound 5 is an example of formula (I). In this general reaction scheme I, 1 reacts with an amine, such as intermediate 2 , and the reaction may be, for example, a nucleophilic substitution or a metal-catalyzed reaction to produce compound 3 . Subsequently, compound 3 can undergo a metal-catalyzed reaction with a coupling partner (such as a boronic acid derivative YR ³ 4 ) in the presence of a suitable base, such as sodium carbonate, to form the title compound 5 . General reaction scheme II

For general reaction scheme II, compound 5 is an example of formula (I). In this general reaction scheme II, 6 is reacted with an amine, such as intermediate 2 , and this reaction can be, for example, a nucleophilic substitution or a metal-catalyzed reaction to produce compound 7 . Subsequently, the compound 7 may be suitable base, for example in the presence of sodium carbonate, with a coupling partner (e.g. boronic acid derivative YR ¹ 8) metal-catalyzed reaction to form the title compound 5. General reaction scheme III

For general reaction scheme III, compound 5 is an example of formula (I). In this general reaction Scheme III, Compound 7 may be of suitable base, for example in the presence of cesium carbonate, with a coupling partner (e.g., an alcohol or an amine, HR ¹ 9) or metal-catalyzed nucleophilic substitution reaction, to provide the title Compound 5 . General reaction scheme IV

For general reaction scheme IV, compound 5 is an example of formula (I). In this general reaction scheme IV, compound 10 is reacted with an amine, such as intermediate 2 , which reaction may be, for example, a nucleophilic substitution or a metal-catalyzed reaction to form the title compound 5 . General reaction scheme V

For general reaction scheme V, compound 5 is an example of formula (I). In this general reaction scheme V, 11 is reacted with an amine, such as Intermediate 2 , and the reaction can be, for example, a nucleophilic substitution or a metal-catalyzed reaction to produce compound 12 . Subsequently, compound 12 can undergo a metal-catalyzed reaction ^{with a coupling partner such as a boric acid derivative YR 3} 4 in the presence of a suitable base, such as sodium carbonate , to form compound 7 . Subsequently, the compound 7 may be suitable base, for example in the presence of sodium carbonate, with a coupling partner (e.g. boronic acid derivative YR ¹ 8) metal-catalyzed reaction to form the title compound 5. General reaction scheme VI

For general reaction scheme VI, compound 5 is an example of formula (I). In this general reaction scheme VI, compound 13 can be combined with a coupling partner such as alcohol, halide, tosylate or methanesulfonate in the presence of a suitable base or coupling partner such as cesium carbonate or diethyl azodicarboxylate. ester substitution reaction XR ¹ 14, to provide the title compound 5.

The following intermediates can be used to prepare the compounds of the present invention. Intermediate A

_{Step A: Add Boc 2} dropwise to a mixture of 1-(2-bromophenyl) -N -methylmethylamine (6.50 g, 32.5 mmol, 1 equivalent) in THF (70.0 mL) at 25°C O (7.80 g, 35.7 mmol, 8.21 mL, 1.10 equivalents), and the mixture was stirred at 25°C for 1 hour . The reaction mixture was directly concentrated in vacuo to obtain a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 20/1 to 10/1) to obtain (2-bromobenzyl)(methyl)amine as a colorless oil Tert-butyl formate (7.50 g, 25.0 mmol, 76.9% yield).

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.55 (br d, J = 8.0 Hz, 1H), 7.34-7.28 (m, 1H), 7.22-7.08 (m, 2H), 4.61-4.42 (m, 2H) , 2.94-2.78 (m, 3H), 1.60-1.33 (m, 9H).

烷（80.0 mL）中之混合物脫氣，且用氮氣沖洗3次，且隨後將混合物在氮氣氛圍下在110℃下攪拌12小時。將反應混合物在減壓下濃縮，得到殘餘物，且將殘餘物藉由管柱層析法（SiO₂ ，石油醚/乙酸乙酯＝1/0至10/1）純化，得到呈無色油狀之甲基(2-(4,4,5,5-四甲基-1,3,2-二氧雜環戊硼烷-2-基)苯甲基)胺甲酸第三丁酯（8.00 g，23.0 mmol，98.8%產率）。Step B: Combine tert-butyl (2-bromobenzyl)(methyl)carbamate (7.00 g, 23.3 mmol, 1.00 equivalent), double pinacol borate (8.88 g, 35.0 mmol, 1.50 equivalent) ), Pd(dppf)Cl ₂ (1.71 g, 2.33 mmol, 0.10 equivalent) and potassium acetate (5.72 g, 58.3 mmol, 2.50 equivalent) in two

The mixture in alkane (80.0 mL) was degassed and flushed with nitrogen 3 times, and then the mixture was stirred at 110° C. for 12 hours under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure to obtain a residue, and the residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 1/0 to 10/1) to obtain a colorless oil Methyl (2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl) tertiary butyl carbamate (8.00 g , 23.0 mmol, 98.8% yield).

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.82 (br d, J = 7.2 Hz, 1H), 7.48-7.37 (m, 1H), 7.27-7.21 (m, 2H), 4.85-4.63 (m, 2H) , 2.92-2.73 (m 3H), 1.54-1.41 (m, 9H), 1.35 (s, 12H). Intermediate B

Step A: To 1-(4-bromothiophen-2-yl)ethan-1-one (4.00 g, 19.5 mmol, 1.10 equivalents) and 2-methylpropane-2-sulfinamide (2.15 g, 17.7 mmol _{, 1.00 equivalent) Ti(OEt) 4} (8.09 g, 35.5 mmol, 7.35 mL, 2.00 equivalent) was added to a solution in THF (56.0 mL). The mixture was stirred at 70°C for 2 hours. The mixture was poured into water (15.0 mL) and stirred for 5 minutes. The suspension was filtered, and the filtrate was concentrated in vacuo to give a residue. The residue was washed with petroleum ether/ethyl acetate=5/1 (10 mL), filtered, and the filter cake was collected and dried in vacuo to give N -(1-(4-bromothiophene-2- Ethyl)-2-methylpropane-2-sulfinamide (3.00 g, 9.73 mmol, 54.9% yield).

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.43 (d, J = 1.2 Hz, 1H), 7.41 (d, J = 1.2 Hz, 1H), 2.72 (s, 3H), 1.30 (s, 9H).

Step B: At 0°C, add N -(1-(4-bromothiophen-2-yl)ethyl)-2-methylpropane-2-sulfinamide (3.70 g, 12.0 mmol, 1.00 equivalent ) To a solution in THF (40.0 mL) was added sodium borohydride (1.36 g, 36.0 mmol, 3.00 equivalents). The reaction mixture was slowly warmed to 25°C and stirred for 2 hours. The mixture was poured into ice water (15.0 mL) and stirred at 0°C for 5 minutes. The aqueous phase was extracted with ethyl acetate (30.0 mL×3). The combined organic phase was washed with brine (30.0 mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to obtain N- (1-(4-bromothiophen-2-yl)ethyl as a yellow oil )-2-Methylpropane-2-sulfinamide (3.60 g, 9.51 mmol, 79.3% yield, 82.0% purity).

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.15 (s, 1H), 6.98-6.96 (s, 1H), 4.81-4.75 (m, 1H), 3.55 (br d, J = 3.6 Hz, 1H), 1.59 (d, J = 6.4 Hz, 3H), 1.24 (s, 9H).

烷（35.0 mL）及水（8.00 mL）中之溶液中添加Pd(PPh₃ )₄ （1.12 g，967 µmol，0.10當量）及碳酸銫（9.45 g，29.01 mmol，3.00當量）。將混合物在氮氣氛圍下在110℃下攪拌2小時。將混合物過濾，且將濾液真空濃縮，得到殘餘物。將殘餘物藉由管柱層析法（SiO₂ ，石油醚/乙酸乙酯=10/1至1/1）純化，得到呈黃色油狀之(2-(5-(1-((第三丁基亞磺醯基)胺基)乙基)噻吩-3-基)苯甲基)(甲基)胺甲酸第三丁酯（1.40 g，3.11 mmol，32.1%產率）。LCMS [M+1]:  451.2。Step C: Under nitrogen atmosphere, add N- (1-(4-bromothiophen-2-yl)ethyl)-2-methylpropane-2-sulfinamide (3.00 g, 9.67 mmol, 1.00 equivalent) And tert-butyl methyl (2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)carbamate (5.04 g , 14.5 mmol, 1.50 equivalent) in two

_{Add Pd(PPh 3} ) ₄ (1.12 g, 967 µmol, 0.10 equivalent) and cesium carbonate (9.45 g, 29.01 mmol, 3.00 equivalent) to a solution in alkane (35.0 mL) and water (8.00 mL). The mixture was stirred at 110°C for 2 hours under a nitrogen atmosphere. The mixture was filtered, and the filtrate was concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=10/1 to 1/1) to obtain (2-(5-(1-((third (Butylsulfinyl)amino)ethyl)thiophen-3-yl)benzyl)(methyl)carbamate (1.40 g, 3.11 mmol, 32.1% yield). LCMS [M+1]: 451.2.

Step D: To (2-(5-(1-((tert-butylsulfinyl)amino)ethyl)thiophen-3-yl)benzyl)(methyl)carbamate (1.40 g, 4.88 mmol, 1.00 equivalent) To a solution in THF (15.0 mL) and water (5.00 mL) was added iodine (232 mg, 1.46 mmol, 295 µL, 0.30 equivalent). The mixture was stirred at 50°C for 30 minutes. The residue was poured into saturated aqueous sodium sulfite solution (30.0 mL), and stirred for 5 minutes. The aqueous phase was extracted with ethyl acetate (15.0 mL×2). The combined organic phase was washed with brine (30.0 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to obtain (2-(5-(1-aminoethyl)thiophene-3- (Yl)benzyl)(methyl)carbamate (1.20 g, crude).

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.36-7.28 (m, 3H), 7.26-7.22 (m, 1H), 7.01 (s, 1H), 6.91 (br s, 1H), 4.49 (br d, J = 19.2 Hz, 2H), 4.40 (q, J = 6.4 Hz, 1H), 2.72 (br d, J = 19.2 Hz, 3H), 1.53 (d, J = 6.4 Hz, 3H), 1.51-1.40 (m, 9H). Intermediate C and D

Step A: Add 4-bromothiophene-2-carbaldehyde (20.0 g, 104 mmol, 1.00 equivalent) and ( R )-2-methylpropane-2-sulfinamide (12.1 g, 99.5 mmol, 0.95 equivalent) to Add titanium (IV) ethoxide (47.8 g, 209 mmol, 43.4 mL, 2.00 equivalents) to the solution in THF (200 mL). The reaction mixture was stirred at 25°C for 1 hour. The mixture was then poured into water (20.0 mL) and stirred for 5 minutes to obtain a suspension. The suspension was filtered, and the filtered liquid was concentrated in vacuo to obtain ( R , E ) -N -((4-bromothien-2-yl)methylene)-2-methylpropane-2 as a yellow oil -Sulfonamide (20.0 g, crude). LCMS [M+1]: 295.8.

Step B: At 0℃, add ( R , E ) -N -((4-bromothiophen-2-yl)methylene)-2-methylpropane-2-sulfinamide (600 mg, 2.04 mmol, 1.00 equivalent) was added dropwise methylmagnesium bromide (3.00 M, 2.04 mL, 3.00 equivalent) to a solution in THF (200 mL). The reaction mixture was then stirred at 25°C for 1 hour. A saturated aqueous ammonium chloride solution (3.00 mL) was added to the reaction mixture, and stirred for 5 minutes. The aqueous phase was extracted with ethyl acetate (3.00 mL×2), and the combined organic phase was washed with brine (3.00 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to obtain a residue. The residue was purified by preparative TLC (SiO ₂ , petroleum ether/ethyl acetate = 1/1) to obtain ( R ) -N -(( S )-1-(4-bromothiophene- 2-yl)ethyl)-2-methylpropane-2-sulfinamide (first dissolution, intermediate C) (120 mg, 19.0% yield) and ( R ) -N in the form of yellow oil -(( R )-1-(4-Bromothiophen-2-yl)ethyl)-2-methylpropane-2-sulfinamide (second elution, intermediate D) (150 mg, 483 µmol , 23.7% yield).

Intermediate C: ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.15 (d, J = 1.6 Hz, 1H), 6.97 (s, 1H), 4.81-4.75 (m, 1H), 3.51 (br d, J = 3.2 Hz, 1H), 1.59 (d, J = 6.8 Hz, 3H), 1.24 (s, 9H).

Intermediate D: ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.14 (d, J = 1.6 Hz, 1H), 6.89 (s, 1H), 4.81-4.74 (m, 1H), 3.39 (br d, J = 5.6 Hz, 1H), 1.65 (d, J = 6.8 Hz, 3H), 1.25 (s, 9H). Intermediate E

烷（1.00 mL）及水（0.20 mL）中之溶液中添加Pd(PPh₃ )₄ （55.9 mg，48.3 µmol，0.10當量）及碳酸銫（473 mg，1.45 mmol，3.00當量）。將反應混合物在氮氣氛圍下在110℃下攪拌2小時，隨後至25℃且真空濃縮，以得到殘餘物。將殘餘物藉由製備型TLC（SiO₂ ，石油醚/乙酸乙酯= 1/1）純化，得到呈白色固體狀之(2-(5-((R )-1-(((R )-第三丁基亞磺醯基)胺基)乙基)噻吩-3-基)苯甲基)(甲基)胺甲酸第三丁酯（120 mg，266 µmol，55.1%產率）。LCMS [M+1] = 451.1。Step A: Under a nitrogen atmosphere, add ( R ) -N -(( R )-1-(4-bromothien-2-yl)ethyl)-2-methylpropane-2-sulfinamide (150 mg, 483 µmol, 1.00 equivalent) and methyl (2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)amine Tert-butyl formate (168 mg, 483 µmol, 1.00 equivalent) in two

_{Add Pd(PPh 3} ) ₄ (55.9 mg, 48.3 µmol, 0.10 equivalent) and cesium carbonate (473 mg, 1.45 mmol, 3.00 equivalent) to a solution in alkane (1.00 mL) and water (0.20 mL). The reaction mixture was stirred at 110°C for 2 hours under a nitrogen atmosphere, then to 25°C and concentrated in vacuo to obtain a residue. The residue was purified by preparative TLC (SiO ₂ , petroleum ether/ethyl acetate = 1/1) to obtain (2-(5-(( R )-1-((( R )-) as a white solid Tertiary butylsulfinyl)amino)ethyl)thiophen-3-yl)benzyl)(methyl)carbamate (120 mg, 266 µmol, 55.1% yield). LCMS [M+1] = 451.1.

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.37-7.29 (m, 3H), 7.25 (s, 1H), 7.06 (s, 1H), 6.95 (br s, 1H), 4.88-4.81 (m, 1H) , 4.48 (br d, J = 16.0 Hz, 2H), 3.44 (br d, J = 6.0 Hz, 1H), 2.73 (br d, J = 12.8 Hz, 3H), 1.71 (d, J = 6.4 Hz, 3H ), 1.27 (s, 9H), 1.25 (s, 9H).

Step B: To (2-(5-(( R )-1-((( R )-tertiary butylsulfinyl)amino)ethyl)thiophen-3-yl)benzyl)(form Add iodine (20.3 mg, 79.9 µmol, 16.1 µL, 0.30 equivalent) to a solution of tert-butyl carbamate (120 mg, 266 µmol, 1.00 equivalent) in THF (1.00 mL) and water (0.20 mL), And the reaction mixture was stirred at 50°C for 1 hour. The reaction mixture was then cooled to 25°C, poured into a saturated aqueous sodium sulfite solution (2.00 mL), and stirred for 5 minutes. The aqueous phase was extracted with ethyl acetate (3.00 mL×3), and the combined organic phase was washed with brine (3.00 mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to obtain a residue. The residue was purified by preparative HPLC (column: Phenomenex Gemini-NX C18 75×30 mm×3 um; mobile phase: [water (0.1% TFA)-ACN]; B%: 28%-38%), (R )-(2-(5-(1-aminoethyl)thiophen-3-yl)benzyl)(methyl)carbamate (40.0 mg, 113 µmol) was obtained in the form of white oil , 42.3% yield, 97.5% purity).

¹ H NMR (400 MHz, CD ₃ OD) δ 7.41-7.23 (m, 6H), 4.84-4.79 (m, 1H), 4.48 (s, 2H), 2.73 (s, 3H), 1.76 (d, J = 6.8 Hz, 3H), 1.51-1.36 (m, 9H). Intermediate F

烷（1.00 mL）及水（0.20 mL）中之溶液中添加Pd(PPh₃ )₄ （37.2 mg，32.2 µmol，0.10當量）及碳酸銫（315 mg，967 ummol，3.00當量）。將反應混合物在110℃下攪拌2小時，隨後冷卻至25℃且真空濃縮，以得到殘餘物。將殘餘物藉由製備型TLC（SiO₂ ，石油醚/乙酸乙酯= 1/1）純化，得到呈黃色油狀之(2-(5-((S )-1-(((R )-第三丁基亞磺醯基)胺基)乙基)噻吩-3-基)苯甲基)(甲基)胺甲酸第三丁酯（100 mg，266 µmol，68.9%產率）。LCMS [M+1] = 451.1。Step A: Under nitrogen atmosphere, add ( R ) -N -(( S )-1-(4-bromothien-2-yl)ethyl)-2-methylpropane-2-sulfinamide (100 mg, 322 µmol, 1.00 equivalent) and methyl (2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)amine Tert-butyl formate (112 mg, 322 µmol, 1.00 equivalent) in two

_{Add Pd(PPh 3} ) ₄ (37.2 mg, 32.2 µmol, 0.10 equivalent) and cesium carbonate (315 mg, 967 ummol, 3.00 equivalent) to a solution in alkane (1.00 mL) and water (0.20 mL). The reaction mixture was stirred at 110°C for 2 hours, then cooled to 25°C and concentrated in vacuo to obtain a residue. The residue was purified by preparative TLC (SiO ₂ , petroleum ether/ethyl acetate = 1/1) to obtain (2-(5-(( S )-1-((( R )- Tertiary butylsulfinyl)amino)ethyl)thiophen-3-yl)benzyl)(methyl)carbamate (100 mg, 266 µmol, 68.9% yield). LCMS [M+1] = 451.1.

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.37-7.28 (m, 3H), 7.26-7.22 (m, 1H), 7.07 (d, J = 1.2 Hz, 1H), 7.03 (br s, 1H), 4.90 -4.83 (m, 1H), 4.55-4.41 (m, 2H), 3.71-3.55 (m, 1H), 2.80-2.65 (m, 3H), 1.64 (d, J = 6.8 Hz, 3H), 1.52-1.41 (m, 9H), 1.26 (s, 9H).

Step B: To (2-(5-(( S )-1-((( R )-tertiary butylsulfinyl)amino)ethyl)thiophen-3-yl)benzyl)(form Add iodine (16.9 mg, 66.6 µmol, 13.4 µL, 0.30 equivalent) to a solution of tert-butyl carbamate (100 mg, 266 µmol, 1.00 equivalent) in THF (1.00 mL) and water (0.20 mL). The reaction mixture was stirred at 50°C for 1 hour, then cooled to 25°C, and poured into a saturated aqueous sodium sulfite solution (2.00 mL), and stirred for 5 minutes. The aqueous phase was extracted with ethyl acetate (3.00 mL×3), and the combined organic phase was washed with brine (3.00 mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to obtain a residue. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 150×25 mm×10 um; mobile phase: [water (0.1% TFA)-ACN]; B%: 24%-54%). (S )-(2-(5-(1-Aminoethyl)thiophen-3-yl)benzyl)(methyl)carbamate in white oily form (45.0 mg, 97.7 µmol, 44.0 % Yield, TFA salt). LCMS [M+1] = 347.2.

¹ H NMR (400 MHz, CD ₃ OD) δ 7.40 (d, J = 1.2 Hz, 1H), 7.38-7.22 (m, 5H), 4.82-4.80 (br s, 1H), 4.48 (s, 2H), 2.73 (s, 3H), 1.75 (d, J = 6.8 Hz, 3H), 1.50-1.35 (m, 9H). Intermediate G

Step A: Add 2-methyl-3-(trifluoromethyl)benzaldehyde (300 mg, 1.59 mmol, 1.00 equivalent) and 2-methylpropane-2-sulfinamide (213 mg, 1.75 mmol, 1.10 Equivalent) Titanium (IV) ethoxide (727 mg, 3.19 mmol, 661 µL, 2.00 equivalent) was added to the solution in THF (5.00 mL). The reaction mixture was stirred at 25°C for 12 hours. The reaction mixture was poured into water (2.00 mL) and stirred for 5 minutes to obtain a suspension. The suspension was filtered and concentrated in vacuo to give 2-methyl- N- (2-methyl-3-(trifluoromethyl)benzylidene)propane-2-sulfenamide (360 mg, 1.24 mmol, 77.5% yield).

¹ H NMR (400 MHz, CDCl ₃ ) δ = 8.98 (s, 1H), 8.13 (d, J = 7.6 Hz, 1H), 7.78 (d, J = 7.6 Hz, 1H), 7.40 (t, J = 7.6 Hz, 1H), 2.70 (d, J = 0.8 Hz, 3H), 1.29 (s, 9H).

Step B: Add 2-methyl- N- (2-methyl-3-(trifluoromethyl)benzylidene)propane-2-sulfenamide (185 mg , 635 µmol, 1.00 equivalent) in THF (5.00 mL) was added dropwise methylmagnesium bromide (227 mg, 3.00 M, 635 µL, 3.00 equivalent). The reaction mixture was stirred at 25°C for 3 hours and then slowly treated with saturated ammonium chloride solution (10.0 mL). The organic layer and the aqueous phase were separated, and the aqueous phase was extracted with ethyl acetate (5.00 mL×3). The combined organic layer was washed with brine (10.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 10/1 to 1/1) to obtain 2-methyl- N -(1-(2-methyl) as a yellow solid 3-(trifluoromethyl)phenyl)ethyl)propane-2-sulfinamide (150 mg, 488.0 µmol, 76.8% yield).

¹ H NMR (400 MHz, CDCl ₃ ) δ = 7.65-7.54 (m, 4H), 7.35-7.28 (m, 2H), 5.00-4.87 (m, 2H), 2.49 (s, 6H), 1.54-1.50 ( m, 6H), 1.26-1.24 (m, 9H), 1.22 (s, 9H).

烷中，1.00 mL）中之溶液在25℃下攪拌1小時。將反應混合物過濾，且將濾餅真空濃縮，得到呈紅色固體狀之1-(2-甲基-3-(三氟甲基)苯基)乙-1-胺（45.0 mg，38.5%產率）。LCMS [M+1] = 204.3。Step C: Add 2-methyl- N -(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)propane-2-sulfinamide (150 mg, 488.0 µmol, 1.00 Equivalent) in HCl (4.0 M to two

In alkane, the solution in 1.00 mL) was stirred at 25°C for 1 hour. The reaction mixture was filtered, and the filter cake was concentrated in vacuo to give 1-(2-methyl-3-(trifluoromethyl)phenyl)ethan-1-amine (45.0 mg, 38.5% yield) as a red solid ). LCMS [M+1] = 204.3.

¹ H NMR (400 MHz, CD ₃ OD) δ = 7.78-7.65 (m, 2H), 7.56-7.48 (m, 1H), 4.93-4.89 (m, 1H), 2.52 (d, J = 0.8 Hz, 3H ), 1.63 (d, J = 6.8 Hz, 3H). Intermediate H

Step A: Add 1-(2-methyl-3-(trifluoromethyl)phenyl)ethan-1-one (8.00 g, 39.6 mmol, 1.00 equivalent) and ( S )-2-methylpropane-2 -To a solution of sulfinamide (5.28 g, 43.5 mmol, 1.10 equivalents) in THF (80.0 mL) was added titanium (IV) ethoxide (18.1 g, 79.1 mmol, 16.4 mL, 2.00 equivalents). The reaction mixture was stirred at 70°C for 2 hours. The reaction mixture was cooled to 25°C and poured into ice water (w/w=1/1) (80.0 mL), and stirred for 15 minutes to obtain a suspension. The suspension was filtered, and the filtrate was extracted with ethyl acetate (50.0 mL×3). The combined organic phase was washed with brine (30.0 mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to obtain a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=20/1 to 3/1) to obtain ( S )-2-methyl-N-(1- (2-Methyl-3-(trifluoromethyl)phenyl)ethylene)propane-2-sulfinamide (8.00 g, 26.2 mmol, 66.2% yield). LCMS [M+1]: 306.2.

¹ H NMR (400 MHz, CD ₃ OD) δ 7.74 (br t, J = 7.2 Hz, 2H), 7.57-7.51 (m, 1H), 7.46 (br t, J = 7.6 Hz, 2H), 7.43-7.30 (m, 1H), 2.72 (s, 3H), 2.54 ( J = 6.8 Hz, 3H), 2.48 (s, 3H), 2.40 (br d, J = 16.0 Hz, 3H), 1.31 (s, 9H), 1.24 (br d, J = 12.4 Hz, 9H).

Step B: At -78°C, add S )-2-methyl-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethylene)propane-2-sulfinic acid To a solution of amide (8.00 g, 26.2 mmol, 1.00 equivalent) in THF (80.0 mL) was added lithium tri-second butylborohydride (7.47 g, 39.3 mmol, 8.59 mL, 1.50 equivalent) dropwise. The reaction mixture was stirred at -78°C for 2 hours. Water was added to the reaction mixture (10.0 mL) at 0°C, and the resulting mixture was stirred for 5 minutes. The aqueous phase was extracted with ethyl acetate (30.0 mL×3). The combined organic phase was washed with brine (30.0 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to obtain a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 20/1 to 3/1) to obtain ( S )-2-methyl- N -(( R )-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)propane-2-sulfinamide (3.50 g, 11.4 mmol, 43.5% yield). LCMS [M+1]: 308.0.

¹ H NMR (400 MHz, CD ₃ OD) δ = 7.70 (d, J = 8.0 Hz, 1H), 7.57 (d, J =7.6 Hz, 1H), 7.39-7.33 (m, 1H), 4.94-4.88 ( m, 1H), 2.48 (d, J = 1.2 Hz, 3H), 1.54 (d, J = 6.4 Hz, 3H), 1.20 (s, 9H).

烷中，15.0 mL）中之溶液在25℃下攪拌30分鐘。將反應混合物過濾且將濾餅真空乾燥，得到呈白色固體狀之(R )-1-(2-甲基-3-(三氟甲基)苯基)乙-1-胺（700 mg，2.89 mmol， 68.4%產率， 99.1%純度，鹽酸鹽）。LCMS [M+H]: 204.0。Step C: Add S )-2-methyl- N -(( R )-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)propane-2-sulfinamide ( 1.30 g, 4.23 mmol, 1.00 equivalent) in HCl (4 M in two

In alkane, the solution in 15.0 mL) was stirred at 25°C for 30 minutes. The reaction mixture was filtered and the filter cake was dried in vacuo to give ( R )-1-(2-methyl-3-(trifluoromethyl)phenyl)ethan-1-amine (700 mg, 2.89) as a white solid mmol, 68.4% yield, 99.1% purity, hydrochloride). LCMS [M+H]: 204.0.

¹ H NMR (400 MHz, CD ₃ OD) δ = 7.73 (t, J = 7.6 Hz, 2H), 7.54-7.49 (m, 1H), 4.92-4.88 (m, 1H), 2.52 (d, J = 0.8 Hz, 3H), 1.62 (d, J = 6.8 Hz, 3H). Intermediate I

Step A: To a solution of 1-(5-bromothiophen-2-yl)ethan-1-one (11.0 g, 53.6 mmol, 1.00 equivalent) in THF (120 mL) was added 2-methylpropane-2- Sulfonamide (8.45 g, 69.7 mmol, 1.30 equivalents) and titanium(IV) ethoxide (24.5 g, 107 mmol, 22.3 mL, 2.00 equivalents), the reaction mixture was stirred at 75° C. for 12 hours under a nitrogen atmosphere. The reaction mixture was cooled to 25°C and concentrated in vacuo to obtain a residue. The residue was diluted with water (200 mL) and ethyl acetate (200 mL), filtered, and the filtrate was extracted with ethyl acetate (100 mL×3) . The combined organic layer was washed with brine (300 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain N -(1-(5-bromothiophen-2-yl) Ethyl)-2-methylpropane-2-sulfinamide (16.0 g, crude). LCMS [M+1]: 308.0.

Step B: At 0°C, add N -(1-(5-bromothien-2-yl)ethyl)-2-methylpropane-2-sulfinamide (16.0 g, 51.9 mmol, 1.00 equivalent ) Sodium borohydride (3.93 g, 104 mmol, 2.00 equivalents) was added to the solution in THF (150 mL), and the reaction mixture was stirred at 20°C for 1 hour. A saturated aqueous sodium bicarbonate solution (20.0 mL) was added dropwise to the reaction mixture, and then the mixture was diluted with water (200 mL) and extracted with ethyl acetate (100 mL×3). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to obtain a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 30/1 to 2/1) to obtain N -(1-(5-bromothiophene-2- (Yl)ethyl)-2-methylpropane-2-sulfinamide (12.0 g, 38.7 mmol, 74.5% yield). LCMS [M+1]: 309.9. Intermediate J

Step A: To 1-(5-bromothiophen-2-yl)ethan-1-one (10.0 g, 48.8 mmol, 1.00 equivalent) and ( R )-2-methylpropane-2-sulfinamide (7.68 g, 63.4 mmol, 1.30 equivalents) in THF (120 mL) was added titanium (IV) ethoxide (22.3 g, 97.5 mmol, 20.2 mL, 2.00 equivalents), and the reaction mixture was stirred at 70°C under a nitrogen atmosphere 12 hours. The reaction mixture was cooled to 25°C, diluted with water (200 mL) and ethyl acetate (100 mL) to obtain a suspension, the suspension was filtered, and the filtrate was extracted with ethyl acetate (100 mL×3). The combined organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to give ( R , E ) -N -(1-(5-bromothiophen-2-yl)ethylene) as a brown oil -2-Methylpropane-2-sulfinamide (13.0 g, crude). LCMS [M+1]: 308.2.

¹ H NMR (400 MHz, CDCl ₃ ) δ = 7.23 (d, J = 4.0 Hz, 1H), 7.04 (d, J = 4.0 Hz, 1H), 2.67 (s, 3H), 1.28 (s, 9H).

Step B: To ( R , E ) -N -(1-(5-bromothiophen-2-yl)ethylene)-2-methylpropane-2-sulfinamide (13.0 g , 42.2 mmol, 1.00 equivalent) in THF (150 mL) was added sodium borohydride (4.79 g, 127 mmol, 3.00 equivalent). The reaction mixture was stirred at 20°C for 2 hours under a nitrogen atmosphere. To the mixture was added a saturated aqueous sodium bicarbonate solution (20.0 mL) dropwise, and diluted with water (200 mL), the resulting aqueous solution was extracted with ethyl acetate (100 mL×3), and the combined organic layer was dried over sodium sulfate and filtered , And concentrated under vacuum to obtain a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 30/1 to 2/1) to obtain ( R ) -N -(( R )-1- as a brown solid (5-Bromothiophen-2-yl)ethyl)-2-methylpropane-2-sulfinamide (6.00 g, 17.4 mmol, 41.3% yield, 90.0% purity). LCMS [M+1]: 309.9.

¹ H NMR (400 MHz, CDCl ₃ ) δ = 6.90 (d, J = 3.6 Hz, 1H), 6.80 (d, J = 3.6 Hz, 1H), 4.84-4.66 (m, 1H), 3.50 (d, J = 2.8 Hz, 1H), 1.57 (d, J = 6.4 Hz, 3H), 1.23 (s, 9H).

烷（20.0 mL）及水（2.00 mL）中之溶液中添加碳酸銫（6.30 g，19.3 mmol，3.00當量）及Pd(PPh₃ )₄ （745 mg，645 µmol，0.10當量）。將反應混合物在氮氣氛圍下在110℃下攪拌2小時。隨後將反應混合物冷卻至25℃，用水（100 mL）稀釋，且用乙酸乙酯（50.0 mL×3）萃取。將合併之有機層經硫酸鈉乾燥，過濾，且在減壓下濃縮，得到殘餘物。將殘餘物藉由管柱層析法（SiO₂ ，石油醚/乙酸乙酯＝20/1至1/1）純化，得到呈黃色油狀之(2-(5-((R )-1-(((R )-第三丁基亞磺醯基)胺基)乙基)噻吩-2-基)苯甲基)(甲基)胺甲酸第三丁酯（2.60 g，5.19 mmol，80.6%產率，90.0%純度）。LCMS [M+1]: 451.4。Step C: Under a nitrogen atmosphere, add ( R ) -N -(( R )-1-(5-bromothiophen-2-yl)ethyl)-2-methylpropane-2-sulfinamide (2.00 g, 6.45 mmol, 1.00 equivalent) and methyl(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)amine Tert-butyl formate (2.69 g, 7.74 mmol, 1.20 equivalent) in two

Add cesium carbonate (6.30 g, 19.3 mmol, 3.00 equivalents) and Pd(PPh ₃ ) ₄ (745 mg, 645 µmol, 0.10 equivalents) to a solution in alkane (20.0 mL) and water (2.00 mL). The reaction mixture was stirred at 110°C for 2 hours under a nitrogen atmosphere. The reaction mixture was then cooled to 25°C, diluted with water (100 mL), and extracted with ethyl acetate (50.0 mL×3). The combined organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 20/1 to 1/1) to obtain (2-(5-(( R )-1- ((( R )-Tertiary butylsulfinyl)amino)ethyl)thiophen-2-yl)benzyl)(methyl) tert-butyl carbamate (2.60 g, 5.19 mmol, 80.6% Yield, 90.0% purity). LCMS [M+1]: 451.4.

¹ H NMR (400 MHz, CDCl ₃ ) δ = 7.40-7.32 (m, 2H), 7.31-7.27 (m, 1H), 7.26-7.22 (m, 1H), 7.01 (s, 1H), 6.83 (s, 1H), 4.95-4.79 (m, 1H), 4.67-4.44 (m, 2H), 3.56 (d, J = 3.2 Hz, 1H), 2.93-2.56 (m, 3H), 1.64 (d, J = 6.4 Hz , 3H), 1.56-1.36 (m, 9H), 1.26 (s, 9H).

Step D: To (2-(5-(( R )-1-((( R )-tertiary butylsulfinyl)amino)ethyl)thiophen-2-yl)benzyl)(form Add iodine (439 mg, 1.73 mmol, 349 µL, 0.30 equivalent) to a solution in THF (20.0 mL) and water (4.00 mL) with tert-butyl carbamate (2.60 g, 5.77 mmol, 1.00 equivalent), The reaction mixture was stirred at 50°C for 2 hours. The reaction mixture was cooled to 25°C, diluted with saturated sodium bicarbonate (50.0 mL), and extracted with ethyl acetate (20.0 mL×3). The combined organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 10/1 to 0/1) to obtain ( R )-( R )-(2-(5) as a yellow oil -(1-Aminoethyl)thiophen-2-yl)benzyl)(methyl) carbamic acid tert-butyl ester (1.50 g, 3.68 mmol, 63.8% yield, 85.0% purity). LCMS [2M+1]: 693.3.

¹ H NMR (400 MHz, CDCl ₃ ) δ = 7.39-7.31 (m, 2H), 7.30-7.20 (m, 2H), 7.01 (d, J = 2.8 Hz, 1H), 6.81 (d, J = 3.2 Hz , 1H), 4.61-4.48 (m, 3H), 4.04 (s, 2H), 2.73 (s, 3H), 1.64 (d, J = 6.4 Hz, 3H), 1.57-1.33 (m, 9H). Intermediate K

烷（5.00 mL）及水（0.50 mL）中之溶液中添加碳酸銫（1.58 g，4.83 mmol，3.00當量）及Pd(PPh₃ )₄ （186 mg，161 µmol，0.10當量），隨後脫氣且用氮氣沖洗3次。將反應混合物在氮氣氛圍下在110℃下攪拌2小時。完成後，將反應混合物冷卻至25℃，用水（50.0 mL）稀釋且用乙酸乙酯（20.0 mL×3）萃取。將合併之有機層經無水硫酸鈉乾燥，過濾，且在減壓下濃縮，得到殘餘物。將殘餘物藉由管柱層析法（SiO₂ ，石油醚/乙酸乙酯=20/1至0/1）純化，得到呈褐色油狀之N -(1-(5-(2-((二甲基胺基)甲基)苯基)噻吩-2-基)乙基)-2-甲基丙烷-2-亞磺醯胺（450 mg，1.15 mmol，71.3%產率，93.0%純度）。LCMS [M+1]: 365.2。Step A: Add N -(1-(5-bromothiophen-2-yl)ethyl)-2-methylpropane-2-sulfinamide (0.50 g, 1.61 mmol, 1.00 equivalent) and N , N- Dimethyl-1-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methylamine (505 mg, 1.93 mmol, 1.20 equivalent) in two

Add cesium carbonate (1.58 g, 4.83 mmol, 3.00 equivalents) and Pd(PPh ₃ ) ₄ (186 mg, 161 µmol, 0.10 equivalents) to a solution in alkane (5.00 mL) and water (0.50 mL), then degas and Flush with nitrogen 3 times. The reaction mixture was stirred at 110°C for 2 hours under a nitrogen atmosphere. After completion, the reaction mixture was cooled to 25°C, diluted with water (50.0 mL) and extracted with ethyl acetate (20.0 mL×3). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 20/1 to 0/1) to obtain N -(1-(5-(2-(() Dimethylamino)methyl)phenyl)thiophen-2-yl)ethyl)-2-methylpropane-2-sulfinamide (450 mg, 1.15 mmol, 71.3% yield, 93.0% purity) . LCMS [M+1]: 365.2.

Step B: To N -(1-(5-(2-((dimethylamino)methyl)phenyl)thiophen-2-yl)ethyl)-2-methylpropane-2-sulfinyl To a solution of amine (410 mg, 1.12 mmol, 1.00 equivalent) in THF (4.00 mL) was added hydrochloric acid (3.00 M, 375 µL, 1.00 equivalent), and the reaction mixture was stirred at 20°C for 2 hours. After completion, the reaction mixture was diluted with saturated sodium bicarbonate (50.0 mL) and extracted with ethyl acetate (20.0 mL×3). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=10/1 to dichloromethane/methanol=10/1) to obtain 1-(5-(2) as a yellow oil -((Dimethylamino)methyl)phenyl)thiophen-2-yl)ethylamine (200 mg, 691 µmol, 61.5% yield, 90.0% purity).

¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 7.48-7.42 (m, 1H), 7.41-7.36 (m, 1H), 7.34-7.28 (m, 2H), 7.13 (d, J = 3.6 Hz, 1H), 6.96-6.92 (m, 1H), 4.29-4.21 (m, 1H), 3.39 (s, 2H), 2.14 (s, 6H), 1.38 (d, J = 6.4 Hz, 3H). Intermediate L

Step A: Add AIBN ( 145 mg, 884 µmol, 0.10 equivalent) and NBS (1.42 g, 7.96 mmol, 0.9 equivalent). The reaction mixture was stirred at 80°C for 12 hours. The reaction was filtered, and the filtrate was concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 50/1 to 10/1) to obtain 3-bromo-6-chlorofuro[3,4 -c ]pyridine-1( 3H )-one (1.20 g, 4.83 mmol, 54.6% yield). LCMS [M+3]: 249.8.

¹ H NMR (400MHz, CDCl ₃ ) δ = 8.84-8.80 (m, 1H), 7.84 (s, 1H), 7.47 (s, 1H).

-1-醇（800 mg，4.41 mmol，91.2%產率）。LCMS [M+1]⁺ : 182.0。Step B: Add 3-bromo-6-chlorofuro[3,4- c ]pyridine-1(3 H )-one (1.20 g, 4.83 mmol, 1.00 equivalent) in ethanol (20.0 mL) at 0°C Add hydrazine hydrate (370 mg, 7.24 mmol, 359 µL, 1.50 equivalents) to the solution in. The reaction mixture was stirred at 80°C for 30 minutes. The reaction was cooled to 25°C and poured into ice water (1.00 mL) to obtain a suspension. The suspension was filtered, and the filter cake was collected and dried under vacuum to obtain 7-chloropyrido[3,4- d ] as a yellow solid

-1-ol (800 mg, 4.41 mmol, 91.2% yield). LCMS [M+1] ⁺ : 182.0.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 13.08 (br s, 1H), 9.20 (s, 1H), 8.53 (s, 1H), 8.10 (s, 1H).

1-醇（78.0 mg，430 µmol，1.00當量）於乙腈（2.00 mL）中之溶液中添加三氯氧磷（V）（231 mg，1.50 mmol，139 µL，3.50當量）。將反應混合物在80℃下攪拌2小時。將反應冷卻至25℃，倒入飽和碳酸氫鈉水溶液（2.00 mL）中，且在0℃下攪拌5分鐘。用乙酸乙酯（3.00 mL×3）萃取水相。將合併之有機相用鹽水（2.00 mL×3）洗滌，經無水硫酸鈉乾燥，過濾，且真空濃縮，得到呈紅色固體狀之1,7-二氯吡啶并[3,4-d ]嗒

（65.0 mg，粗製）。LCMS [M+1]: 199.8。 中間物M

Step C: At 25℃, to 7-chloropyrido[3,4- d ]

To a solution of 1-alcohol (78.0 mg, 430 µmol, 1.00 equivalent) in acetonitrile (2.00 mL) was added phosphorus oxychloride (V) (231 mg, 1.50 mmol, 139 µL, 3.50 equivalent). The reaction mixture was stirred at 80°C for 2 hours. The reaction was cooled to 25°C, poured into a saturated aqueous sodium bicarbonate solution (2.00 mL), and stirred at 0°C for 5 minutes. The aqueous phase was extracted with ethyl acetate (3.00 mL×3). The combined organic phase was washed with brine (2.00 mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to obtain 1,7-dichloropyrido[3,4- d ] as a red solid

(65.0 mg, crude). LCMS [M+1]: 199.8. Intermediate M

Step A: At 0°C, add bromine (8.96 g, 56.1 mmol, 2.89 mL, 1.10 equivalent) in acetic acid (50.0 mL) for 1.5 hours. The mixture was then slowly warmed to room temperature and stirred for 45 minutes. After completion, the reaction was quenched by pouring into water (700 mL) and stirred for 30 minutes, then the stirring was stopped, and the mixture was filtered after standing for 1 hour. The collected solid was washed with water (100 mL) and washed with aqueous sodium sulfite (100 mL). The solid part was dried, dissolved in hot methanol (300 mL), and the resulting solution was cooled. The cold methanol solution was treated with water (200 mL) to obtain a suspension, the suspension was filtered, the filter cake was collected and dried in vacuo to obtain methyl 2-bromo-4,5-dimethoxybenzoate as a white powder (9.00 g, 32.7 mmol, 64.2% yield). LCMS [M+1]: 275.3.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 7.36 (s, 1H), 7.24 (s, 1H), 3.84 (s, 3H), 3.82 (s, 3H), 3.79 (s, 3H).

Step B: Combine methyl 2-bromo-4,5-dimethoxybenzoate (6.00 g, 21.8 mmol, 1.00 equivalent), 1-(vinyloxy)butane (10.9 g, 109 mmol, 14.0 mL , 5.00 equivalents), Pd(OAc)2 (490 mg, 2.18 mmol, 0.10 equivalents), triphenylphosphine (1.14 g, 4.36 mmol, 0.20 equivalents) and triethylamine (2.65 g, 26.2 mmol, 3.64 mL, 1.20 equivalents) ) The mixture in acetonitrile (60.0) was degassed and flushed with nitrogen 3 times, and then the reaction mixture was stirred at 100°C for 16 hours under a nitrogen atmosphere. The mixture was then cooled to 25°C, filtered, and the filtrate was concentrated under reduced pressure to obtain methyl 2-(1-butoxyvinyl)-4,5-dimethoxybenzoate ( 6.00 g, crude), which was used directly in the next step.

Step C: Mix 2-(1-butoxyvinyl)-4,5-dimethoxybenzoic acid methyl ester (6.00 g, 20.4 mmol, 1.00 equivalent) in hydrochloric acid (10% in water, 61.2 g, 168 A mixture of mmol, 60.0 mL, 8.23 equivalents) and THF (60.0 mL) was stirred at 20°C for 1 hour. The reaction mixture was diluted with water (100 mL), and extracted with ethyl acetate (50.0 mL×3). The combined organic layer was adjusted to pH=7 with saturated aqueous sodium bicarbonate solution, and then the organic layer was washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was wet-milled with petroleum ether/ethyl acetate=5/1 (50.0 mL) at 20°C for 20 minutes to obtain a suspension, the suspension was filtered, the filter cake was collected and vacuum dried to obtain a white solid Methyl 2-acetyl-4,5-dimethoxybenzoate (3.00 g, 12.6 mmol, 61.8% yield).

1H NMR (400 MHz, DMSO-d6) δ = 7.26 (s, 1H), 7.17 (s, 1H), 3.86 (s, 3H), 3.84 (s, 3H), 3.77 (s, 3H), 2.46 (s , 3H).

-1(2H)-酮（2.00 g，9.08 mmol，72.1%產率）。LCMS [M+1]: 221.4。Step D: At room temperature, add hydrazine hydrate to a solution of methyl 2-acetyl-4,5-dimethoxybenzoate (3.00 g, 12.6 mmol, 1.00 equivalent) in ethanol (30.0 mL) (2.22 g, 37.8 mmol, 2.16 mL, 3.00 equivalents), and then the reaction mixture was stirred at 95°C for 30 minutes. The reaction mixture was diluted with water (100 mL) and extracted several times with ethyl acetate. The combined organic layer was washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was wet-milled with ethyl acetate (50.0 mL) at 20°C for 20 minutes to obtain a suspension. The suspension was filtered. The filter cake was collected and dried in vacuo to obtain 6,7-dimethoxy as an off-white solid. -4-methyl

-1(2H)-one (2.00 g, 9.08 mmol, 72.1% yield). LCMS [M+1]: 221.4.

1H NMR (400 MHz, DMSO-d6) δ = 12.25 (s, 1H), 7.58 (s, 1H), 7.21 (s, 1H), 3.96 (s, 3H), 3.92 (s, 3H), 2.48 (s , 3H).

-1(2H)-酮（1.30 g，5.90 mmol，1.00當量）於三氯氧磷（V）（13.0 mL）中之混合物在120℃下攪拌12小時。將反應混合物在減壓下濃縮，得到呈黃色固體狀之1-氯-6,7-二甲氧基-4-甲基呔

（1.20 g，粗製）。LCMS [M+1]: 239.0。Step E: Add 6,7-dimethoxy-4-methyl

A mixture of -1(2H)-ketone (1.30 g, 5.90 mmol, 1.00 equivalent) in phosphorus oxychloride (V) (13.0 mL) was stirred at 120°C for 12 hours. The reaction mixture was concentrated under reduced pressure to obtain 1-chloro-6,7-dimethoxy-4-methyl as a yellow solid

(1.20 g, crude). LCMS [M+1]: 239.0.

1H NMR (400 MHz, DMSO-d6) δ = 7.80 (s, 1H), 7.64 (s, 1H), 4.13 (s, 3H), 4.12 (s, 3H), 3.08 (s, 3H). Intermediate N

Step A: Add ethanol to a solution of 1-(3-(difluoromethyl)-2-methylphenyl)ethan-1-one (0.37 g, 1.99 mmol, 1.00 equivalent) in tetrahydrofuran (10.0 mL) Titanium (IV) (2.27 g, 9.95 mmol, 2.06 mL, 5.00 equivalents) and ( R )-2-methylpropane-2-sulfinamide (724 mg, 5.97 mmol, 3.00 equivalents). The mixture was stirred at 75°C for 16 hours. The reaction mixture was quenched by adding 20.0 mL of saturated aqueous sodium bicarbonate solution at 25°C. The mixture was filtered, and the filtrate was extracted with ethyl acetate 45.0 mL (15.0 mL × 3). The combined organic layer was washed with brine 20.0 mL (20.0 mL×1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by rapid silica gel chromatography (0-12% ethyl acetate/petroleum ether ) to obtain (R , E ) -N -(1-(3-(difluoromethyl) as a colorless oil -2-Methylphenyl)ethyl)-2-methylpropane-2-sulfinamide (0.36 g, 1.19 mmol, 59.8% yield, 95.0% purity).

¹ H NMR (400 MHz, CD ₃ OD) δ = 7.55-7.62 (m, 1H), 7.16-7.51 (m, 2H), 6.79-7.13 (m, 1H), 2.48-2.73 (m, 3H), 2.27 -2.47 (m, 3H), 1.19-1.30 (m, 9H).

Step B: To ( R , E ) -N -(1-(3-(difluoromethyl)-2-methylphenyl)ethyl)-2-methylpropane-2-sulfinamide ( To a solution of 340 mg, 1.18 mmol, 1.00 equivalent) in tetrahydrofuran (5.00 mL) was added sodium borohydride (89.5 mg, 2.37 mmol, 2.00 equivalent). The mixture was stirred at 0°C for 1 hour. The reaction mixture was quenched by adding 10.0 mL of water at 25°C, followed by extraction with 30.0 mL (10.0 mL×3) of ethyl acetate. The combined organic layer was washed with brine (10.0 mL×1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by flash silica gel chromatography (0-13% ethyl acetate/petroleum ether) to obtain ( R ) -N -(( R )-1-(3-(difluoromethyl) as a yellow oil (Methyl)-2-methylphenyl)ethyl)-2-methylpropane-2-sulfinamide (190 mg, 643 µmol, 54.4% yield, 98.0% purity). LCMS [M+1] ⁺ = 290.1.

烷鹽酸鹽（4.00 M，7.00 mL，57.9當量）中之混合物在25℃下攪拌1小時。將反應混合物在減壓下濃縮，得到呈白色固體狀之粗產物(R )-1-(3-(二氟甲基)-2-甲基苯基)乙-1-胺（110 mg，475 µmol，98.2%產率，80.0%純度），其無需進一步純化即可使用。LCMS [M+1]⁺ = 186.0。 中間物O

Step C: Add ( R ) -N -(( R )-1-(3-(Difluoromethyl)-2-methylphenyl)ethyl)-2-methylpropane-2-sulfinamide (140 mg, 484 µmol, 1.00 equivalent) in two

The mixture of alkane hydrochloride (4.00 M, 7.00 mL, 57.9 equivalents) was stirred at 25°C for 1 hour. The reaction mixture was concentrated under reduced pressure to give the crude product ( R )-1-(3-(difluoromethyl)-2-methylphenyl)ethan-1-amine (110 mg, 475 µmol, 98.2% yield, 80.0% purity), it can be used without further purification. LCMS [M+1] ⁺ = 186.0. Intermediate O

Step A: Add 3-bromo-2-methylbenzoic acid (100 g, 465 mmol, 1.00 equivalent) and N ,O-dimethylhydroxylamine hydrochloride (68.6 g, 512 mmol, 1.10 equivalent, HCl) in DMF (1000 mL) add 1-[bis(dimethylamino)methylene]-1 H -1,2,3-triazolo[4,5- b ]pyridinium 3-hexaoxide Fluorophosphate (195 g, 512 mmol, 1.10 equivalents) and N,N -diisopropylethylamine (180 g, 1.40 mol, 243 mL, 3.00 equivalents). The mixture was stirred at 25°C for 2 hours, then poured into water (1000 mL) and stirred for 15 minutes. The aqueous phase was extracted with ethyl acetate (1000 mL×3). The combined organic phase was washed with brine (1000 mL×5), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to obtain 3 3-bromo- N -methoxy- N ,2-dimethyl as a yellow oil Benzamide (120 g, crude). LCMS [M+1] ⁺ : 258.0.

Step B: To a solution of 33-bromo- N -methoxy- N ,2-dimethylbenzamide (120 g, 465 mmol, 1.00 equivalent) in THF (100 mL) at 0°C Add methylmagnesium bromide (3.0 M, 180 mL, 1.16 equivalents). The mixture was stirred between 0-40°C for 3 hours, then the mixture was cooled to 0°C and hydrochloric acid (6.0 N) (450 mL) was added dropwise, and stirred between 40-45°C for 2 hours. The mixture was then cooled to 25°C and poured into saturated ammonium chloride solution (9000 mL). The aqueous phase was extracted with ethyl acetate (1500 mL×3). The combined organic phase was washed with brine (1000 mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain 1-(3-bromo-2-methylphenyl)ethyl as a yellow oil -1-one (90.0 g, 422 mmol, 90.9% yield).

¹ H NMR (400 MHz, CD ₃ OD) δ = 7.70 (dd, J = 1.2, 8.0 Hz, 1H), 7.62 (dd, J = 0.8, 7.6 Hz, 1H), 7.19 (t, J = 8.0 Hz, 1H), 2.56 (s, 3H), 2.46 (s, 3H).

Step C: To 1-(3-bromo-2-methylphenyl)ethan-1-one (88.0 g, 413 mmol, 1.00 equivalent) and ( S )-2-methylpropane-2-sulfinamide (60.1 g, 496 mmol, 1.20 equivalents) in THF (100 mL) was added titanium (IV) ethoxide (471 g, 2.07 mol, 428 mL, 5.00 equivalents) and diglyme (55.4 g, 413 mmol, 59.1 mL, 1.00 equivalent). The mixture was stirred at 80°C for 2 hours, then poured into water (300 mL) and stirred for 15 minutes. The mixture was then filtered and concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 100/1 to 40/1) to obtain ( S ) -N -(1-(3-bromo -2-Methylphenyl)ethylene)-2-methylpropane-2-sulfinamide (110 g, 348 mmol, 84.2% yield).

¹ H NMR (400 MHz, CD ₃ OD) δ = 7.63 (br t, J = 6.8 Hz, 2H), 7.28 (br d, J = 7.6 Hz, 1H), 7.17 (t, J = 8.0 Hz, 2H) , 7.14-7.02 (m, 1H), 2.67 (s, 3H), 2.50 (br d, J = 4.8 Hz, 3H), 2.42 (s, 3H), 2.31 (br d, J = 17.2 Hz, 3H), 1.31-1.26 (m, 9H), 1.24-1.16 (m, 9H)

Step D: To ( S ) -N -(1-(3-bromo-2-methylphenyl)ethyl)-2-methylpropane-2-sulfinamide (109 g, 345 mmol, 1.00 equivalent) in THF (1100 mL) was added lithium tri-second butyl borohydride (1.0 M, 689 mL, 2.00 equivalent). The mixture was stirred at -78°C for 2 hours, then poured into a saturated aqueous ammonium chloride solution (1000 mL), and stirred at 25°C for 60 minutes. The aqueous phase was extracted with ethyl acetate (1000 mL×3). The combined organic phase was washed with brine (500 mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 100/1 to 2/1) to obtain a residue. The residue was further washed with petroleum ether to obtain ( S ) -N -(( R )-1-(3-bromo-2-methylphenyl)ethyl)-2-methylpropane- as a white solid 2-sulfinamide (70.0 g, 220 mmol, 63.8% yield). LCMS [M+1] ⁺ : 318.1.

烷溶液（300 mL）及MeOH（300 mL）中之溶液在0℃下攪拌30分鐘。將混合物真空濃縮，得到呈白色固體狀之(R )-1-(3-溴-2-甲基苯基)乙-1-胺（55.0g，粗製，HCl）。LCMS [M+1]⁺ : 214.1。Step E: Add ( S ) -N -(( R )-1-(3-bromo-2-methylphenyl)ethyl)-2-methylpropane-2-sulfinamide (71.0 g, 223 mmol, 1.00 equivalent) in HCl/two

The alkane solution (300 mL) and the solution in MeOH (300 mL) were stirred at 0°C for 30 minutes. The mixture was concentrated in vacuo to give ( R )-1-(3-bromo-2-methylphenyl)ethan-1-amine (55.0 g, crude, HCl) as a white solid. LCMS [M+1] ⁺ : 214.1.

Step F: To ( R )-1-(3-bromo-2-methylphenyl)ethan-1-amine (55.0 g, 220 mmol, 1.00 equivalent, HCl) and Boc ₂ O (48.4 g, 222 mmol, 50.9 mL, 1.01 equivalent) in dichloromethane (500 mL) was added N,N -diisopropylethylamine (56.7 g, 439 mmol, 76.5 mL, 2.00 equivalent). The mixture was stirred between 0-25°C for 30 minutes and then concentrated under vacuum to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 1/0 to 100/1) to obtain a residue. The residue was further washed with petroleum ether to obtain tert-butyl (R )-(1-(3-bromo-2-methylphenyl)ethyl)carbamate (51.0 g, 162 mmol, 73.9% yield). LCMS [M-55] ⁺ : 258.0.

¹ H NMR (400 MHz, CD ₃ OD) δ = 7.43 (d, J = 8.0 Hz, 1H), 7.32 (d, J = 8.0 Hz, 1H), 7.10-7.03 (m, 1H), 4.93 (br d , J = 6.4 Hz, 2H), 2.45 (s, 3H), 1.41 (br s, 9H), 1.33 (d, J = 6.8 Hz, 3H).

Step G: To ( R )-(1-(3-bromo-2-methylphenyl)ethyl) carbamic acid tert-butyl ester (51.0 g, 162 mmol, 1.00 equivalent) in DMF (540 mL) Zinc cyanide (22.9 g, 195 mmol, 12.4 mL, 1.20 equivalents) and Pd(PPh ₃ ) ₄ (18.8 g, 16.2 mmol, 0.10 equivalents) were added to the solution. The mixture was stirred at 110°C for 3 hours, then cooled to 25°C and poured into water (500 mL). The aqueous phase was extracted with ethyl acetate (100 mL×3). The combined organic phase was washed with brine (1000 mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 100/1 to 5/1) to obtain ( R )-(1-(3-cyano- Tertiary butyl 2-methylphenyl)ethyl)carbamate (37.0 g, 142.1 mmol, 87.6% yield). LCMS [M-55] ⁺ : 205.0.

¹ H NMR (400 MHz, CD ₃ OD) δ = 7.63 (d, J = 7.6 Hz, 1H), 7.54 (d, J = 7.2 Hz, 1H), 7.39-7.30 (m, 1H), 4.93 (br d , J = 6.8 Hz, 1H), 2.58 (s, 3H), 1.40 (br s, 9H), 1.34 (d, J = 7.2 Hz, 3H).

Step H: To ( R )-(1-(3-cyano-2-methylphenyl)ethyl) carbamic acid tert-butyl ester (49.0 g, 188 mmol, 1.00 equivalent) in dichloromethane (400 mL Add TFA (133 mL) to the solution in ). The mixture was stirred at 0°C for 30 minutes, then poured into saturated sodium bicarbonate solution (200 mL), and stirred for another 30 minutes. The aqueous phase was extracted with ethyl acetate (1000 mL×3). The combined organic phase was washed with brine (200 mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain (R)-3-(1-aminoethyl)- as a yellow oil 2-methylbenzonitrile (26.0 g, 162 mmol, 86.2% yield). LCMS [M-16] ⁺ : 144.1.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 8.36 (br s, 2H), 7.86 (d, J = 8.0 Hz, 1H), 7.80 (dd, J = 0.8, 7.6 Hz, 1H), 7.51 ( t, J = 8.0 Hz, 1H), 4.68 (q, J = 6.8 Hz, 1H), 2.55 (s, 3H), 1.48 (d, J = 6.8 Hz, 3H).

SFC conditions: column: Chiralpak IC-3, 50×4.6 mm inner diameter, 3 µm; mobile phase: phase A is CO ₂ and phase B is MeOH (0.05% DEA); gradient dissolution: MeOH (0.05% DEA) In 5% to 40% CO ₂ ; flow rate: 3 ml/min; detector: PDA; column temperature: 35°C; back pressure: 100 Bar. Intermediate P

（21.4 g，99.9 mmol，1.00當量）於DMSO（130 mL）中之溶液中添加氟化銫（22.8 g，150 mmol，5.52 mL，1.50當量），且將混合物在130℃下攪拌2小時。隨後將混合物冷卻至25℃，用水（200 mL）稀釋，且用乙酸乙酯（200 mL×3）萃取。將合併之有機相用鹽水（100 mL×3）洗滌，經無水硫酸鈉乾燥，過濾，且在減壓下濃縮。將殘餘物藉由製備型HPLC[管柱：Kromasil Eternity XT 250×80 mm×10 um；移動相：A相：水（0.1% TFA），B相：乙腈；B%：25%-55%]純化。將合併之溶離份合併，且用碳酸氫鈉水溶液將pH調節至pH＝8。將懸浮液用乙酸乙酯（1000 mL×3）萃取，且將合併之有機相用鹽水（100 mL×3）洗滌，經無水硫酸鈉乾燥，過濾，且在減壓下濃縮，得到呈黃色固體狀之(R )-3-(1-((7-氯-4-甲基吡啶并[3,4-d ]嗒

-1-基)胺基)乙基)-2-甲基苯甲腈（14.5 g，42.9 mmol，43.0%產率）。To ( R )-3-(1-aminoethyl)-2-methylbenzonitrile (16.0 g, 99.9 mmol, 1.00 equivalent) and 1,7-dichloro-4-methylpyrido[3, 4- d ]

(21.4 g, 99.9 mmol, 1.00 equiv.) To a solution in DMSO (130 mL) was added cesium fluoride (22.8 g, 150 mmol, 5.52 mL, 1.50 equiv), and the mixture was stirred at 130°C for 2 hours. The mixture was then cooled to 25°C, diluted with water (200 mL), and extracted with ethyl acetate (200 mL×3). The combined organic phase was washed with brine (100 mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to preparative HPLC [column: Kromasil Eternity XT 250×80 mm×10 um; mobile phase: phase A: water (0.1% TFA), phase B: acetonitrile; B%: 25%-55%] purification. The combined fractions were combined, and the pH was adjusted to pH=8 with aqueous sodium bicarbonate solution. The suspension was extracted with ethyl acetate (1000 mL×3), and the combined organic phase was washed with brine (100 mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a yellow solid ( R )-3-(1-((7-chloro-4-methylpyrido[3,4- d ]

-1-yl)amino)ethyl)-2-methylbenzonitrile (14.5 g, 42.9 mmol, 43.0% yield).

向(R )-3-(1-胺基乙基)-2-甲基苯甲腈（5.32 g，19.4 mmol，1.00當量，TFA）及6-溴-4-氯-1-甲基呔

（5.00 g，19.4 mmol，1.00當量）於DMSO（30.0 mL）中之溶液中添加氟化銫（5.90 g，38.8 mmol，1.43 mL，2.00當量）及N,N- 二異丙基乙胺（5.02 g，38.8 mmol，6.76 mL，2.00當量），且將混合物在130℃下攪拌2小時。隨後將混合物冷卻至25℃，用水（10.0 mL）稀釋，且用乙酸乙酯（100 mL×3）萃取水相。將合併之有機相用鹽水（100 mL×3）洗滌，經無水硫酸鈉乾燥，過濾，且在減壓下濃縮。將殘餘物藉由管柱層析法（SiO₂ ，石油醚/乙酸乙酯=20/1至2/1）純化，得到呈黃色固體狀之(R )-3-(1-((7-溴-4-甲基呔

-1-基)胺基)乙基)-2-甲基苯甲腈（5.20 g，13.6 mmol，70.2%產率）。LCMS [M+1]⁺ : 381.1。 中間物R

¹ H NMR (400 MHz, CDCl ₃ ) δ = 9.19 (d, J = 0.4 Hz, 1H), 7.74 (s, 1H), 7.63 (d, J = 8.0 Hz, 1H), 7.50 (dd, J = 1.2 , 7.6 Hz, 1H), 7.23 (t, J = 7.6 Hz, 1H), 5.72 (quin, J = 6.8 Hz, 1H), 5.40 (br d, J = 6.0 Hz, 1H), 2.86 (s, 3H) , 2.69 (s, 3H), 1.63 (s, 3H). Intermediate Q

To ( R )-3-(1-aminoethyl)-2-methylbenzonitrile (5.32 g, 19.4 mmol, 1.00 equivalent, TFA) and 6-bromo-4-chloro-1-methyl

(5.00 g, 19.4 mmol, 1.00 equivalent) in DMSO (30.0 mL) was added cesium fluoride (5.90 g, 38.8 mmol, 1.43 mL, 2.00 equivalent) and N,N -diisopropylethylamine (5.02 g, 38.8 mmol, 6.76 mL, 2.00 equivalents), and the mixture was stirred at 130°C for 2 hours. The mixture was then cooled to 25°C, diluted with water (10.0 mL), and the aqueous phase was extracted with ethyl acetate (100 mL×3). The combined organic phase was washed with brine (100 mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 20/1 to 2/1) to obtain ( R )-3-(1-((7- Bromo-4-methyl

-1-yl)amino)ethyl)-2-methylbenzonitrile (5.20 g, 13.6 mmol, 70.2% yield). LCMS [M+1] ⁺ : 381.1. Intermediate R

Step A: Combine (R )-2-methylpropane-2-sulfinamide (5.12g, 42.2mmol, 1.00 equivalent), 1-(3-bromo-2-methylphenyl)ethan-1-one (9.00 g, 42.2 mmol, 1.00 equivalent), a mixture of titanium(IV) isopropoxide (60.0 g, 211 mmol, 62.3 mL, 5.00 equivalent) in THF (90.0 mL) was degassed and flushed with nitrogen 3 times, and Stir at 80°C for 12 hours. The mixture was cooled to 25°C, quenched by the addition of water (100 mL), filtered, and the filtrate was partitioned between ethyl acetate (300 mL) and water (300 mL). The organic phase was dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=1/0 to 5/1) to obtain ( R ) -N -(1-(3-bromo) as a yellow solid -2-methylphenyl)ethylene)-2-methylpropane-2-sulfinamide (7.23 g, 22.8 mmol, 54.1% yield). LCMS [M+3] ⁺ : 318.0.

¹ H NMR (400 MHz, CD ₃ OD) δ = 7.67-7.58 (m, 2H), 7.28 (br d, J = 7.6 Hz, 1H), 7.17 (t, J = 8.0 Hz, 2H), 7.14-7.01 (m, 1H), 2.67 (s, 3H), 2.50 (br d, J = 4.0 Hz, 3H), 2.42 (s, 3H), 2.31 (br d, J = 17.2 Hz, 3H), 1.28 (s, 9H), 1.21 (br d, J = 11.2 Hz, 9H). (The ratio of E/Z isomers is ~1/1).

Step B: To ( R ) -N -(1-(3-bromo-2-methylphenyl)ethylene)-2-methylpropane-2-sulfinamide (400 mg , 1.26 mmol, 1.00 equivalent) in THF (5.00 mL) was added portionwise sodium borohydride (239 mg, 6.32 mmol, 5.00 equivalent), and then the reaction was stirred at 25°C for 1 hour. The reaction mixture was poured into water (30.0 mL) and stirred for 5 minutes. The resulting aqueous phase was extracted with ethyl acetate (150 mL×3), and the combined organic phase was washed with brine (150 mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 10/1 to 1/1) to obtain ( R ) -N -(( R )-1- (3-Bromo-2-methylphenyl)ethyl)-2-methylpropane-2-sulfinamide (200 mg, 628 µmol, 49.7% yield).

Step C: At 20 ℃, to ( R ) -N -(( R )-1-(3-bromo-2-methylphenyl)ethyl)-2-methylpropane-2-sulfinamide (250 mg, 786 µmol, 1.00 equivalent), sodium methanesulfinate (176 mg, 1.73 mmol, 2.20 equivalent), potassium carbonate (326 mg, 2.36 mmol, 3.00 equivalent) and L- proline (18.1 mg, 157 µmol, 0.20 equivalent) was added to the mixture of dimethyl sulfite (3.00 mL) with cuprous(I) iodide (15.0 mg, 78.6 µmol, 0.10 equivalent), and the mixture was stirred at 130°C under a nitrogen atmosphere for 3 Hour. To the mixture was added water (15.0 mL), and the mixture was extracted with ethyl acetate (20.0 mL×3). The combined organic phase was washed with brine (30.0 mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by preparative TLC (silica gel plate, petroleum ether/ethyl acetate = 1/1) to obtain ( R )-2-methyl- N -(( R )-1-( 2-Methyl-3-(methylsulfonyl)phenyl)ethyl)propane-2-sulfinamide (120 mg, 378 µmol, 48.1% yield). LCMS [M+1] ⁺ : 318.1.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 7.85 (dd, J = 8.0, 1.2 Hz, 1H), 7.78 (d, J = 7.6 Hz, 1H), 7.46 (t, J = 8.0 Hz, 1 H), 5.42-5.50 (m, 1H), 4.71-4.80 (m, 1H), 3.22 (s, 3H), 2.65 (s, 3H), 1.46 (d, J = 6.8 Hz, 3 H), 1.09 ( s, 9H).

烷中，2.00 mL，21.2當量）中之混合物在20℃下攪拌1小時。將混合物在減壓下濃縮，得到呈白色固體狀之(R )-1-(2-甲基-3-(甲基磺醯基)苯基)乙-1-胺（91.0 mg，粗製，HCl）。 中間物S

Step D: Add ( R )-2-methyl- N -(( R )-1-(2-methyl-3-(methylsulfonyl)phenyl)ethyl)propane-2-sulfinyl Amine (120mg, 378 µmol, 1.00 equivalent) in hydrochloric acid (4.0 M in two

In alkane, 2.00 mL, 21.2 equivalents) was stirred at 20°C for 1 hour. The mixture was concentrated under reduced pressure to give ( R )-1-(2-methyl-3-(methylsulfonyl)phenyl)ethan-1-amine (91.0 mg, crude, HCl as a white solid) ). Intermediate S

Step A: Add N , N -diisopropylethylamine (237 g, 1.84 mol, 3.73 equivalents) to a solution of methylamine (100 g, 1.48 mol, 3.01 equivalents, HCl salt) in THF (1.00 L) , 2-Bromo-6-fluorobenzaldehyde (100 g, 493 mmol, 1.00 equivalent), acetic acid (9.00 g, 150 mmol, 0.30 equivalent) and sodium cyanoborohydride (62.0 g, 987 mmol, 2.00 equivalent). The reaction mixture was stirred at 25°C for 3 hours, then diluted with water (500 mL), and extracted with ethyl acetate (1.00 L×2). The combined organic phase was washed with brine (500 mL), dried over sodium sulfate, filtered, and concentrated under vacuum to give 1-(2-bromo-6-fluorophenyl) -N -methyl as an off-white solid Methylamine (120 g, 484 mmol, 88% purity), which was used directly in the next step. LCMS [M+1] ⁺ : 218.0.

Step B: To a solution of 1-(2-bromo-6-fluorophenyl) -N -methylmethylamine (120 g, 484 mmol, 88% purity, 1.00 equivalent) in THF (1.00 L) was added two Di-tert-butyl carbonate (211 g, 968 mmol, 2.00 equivalents), and the mixture was stirred at 25°C for 2 hours. The mixture was then concentrated in vacuo to obtain a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 1/0 to 100/1) to obtain N -[(2-bromo-6-fluoro-benzene Yl)methyl] -N -methyl-carbamic acid tert-butyl ester (70.0 g, 220 mmol). LCMS [M-55]+: 261.9

¹ H NMR (400 MHz, DMSO-d6) δ = 7.49 (d, J = 7.6 Hz, 1H), 7.33-7.26 (m, 2H), 4.57 (s, 2H), 2.64 (s, 3H), 1.38 ( s, 9H).

烷（600 mL）中之溶液中添加Pd(dppf)Cl₂ ·CH₂ Cl₂ （15.0 g，18.4 mmol，0.10當量）及乙酸鉀（72.0 g，734 mmol，3.89當量）。將反應混合物用氮氣脫氣（3次），且在氮氣氛圍下在100℃下攪拌12小時。將混合物冷卻至25℃，且在真空下濃縮，得到殘餘物。將殘餘物藉由管柱層析法（SiO₂ ，石油醚/乙酸乙酯＝1/0至100/1）純化，得到呈黃色油狀之(2-氟-6-(4,4,5,5-四甲基-1,3,2-二氧雜環戊硼烷-2-基)苯甲基)(甲基)胺甲酸第三丁酯（80.0 g，160 mmol，73%純度）。LCMS [M-55]⁺ : 266.1。Step C: To tert-butyl (2-bromo-6-fluorobenzyl)(methyl)carbamate (60.0 g, 189 mmol, 1.00 equivalent) and 4,4,4',4',5,5 ,5',5'-octamethyl-2,2'-bi(1,3,2-dioxole) (60.0 g, 236 mmol, 1.25 equivalents) in two

_{Add Pd(dppf)Cl 2} ·CH ₂ Cl ₂ (15.0 g, 18.4 mmol, 0.10 equivalent) and potassium acetate (72.0 g, 734 mmol, 3.89 equivalent) to the solution in alkane (600 mL). The reaction mixture was degassed with nitrogen (3 times), and stirred at 100° C. for 12 hours under a nitrogen atmosphere. The mixture was cooled to 25°C and concentrated under vacuum to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 1/0 to 100/1) to obtain (2-fluoro-6-(4,4,5) as a yellow oil ,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)(methyl)carbamate (80.0 g, 160 mmol, 73% purity) . LCMS [M-55] ⁺ : 266.1.

烷（500 mL）及水（100 mL）中之溶液中添加碳酸銫（150 g，460 mmol，2.88當量）及Pd(PPh₃ )₄ （20.0 g，17.3 mmol，0.10當量），且將混合物在氮氣氛圍下在100℃下攪拌3小時。將混合物用水（500 mL）稀釋，用乙酸乙酯（1.00 L×2）萃取，將有機相用鹽水（200 mL）洗滌，經硫酸鈉乾燥，過濾且真空濃縮，得到殘餘物。將殘餘物藉由管柱層析法（SiO₂ ，石油醚/乙酸乙酯＝0/1至5/1）純化，得到呈黃色油狀之(2-(5-((R )-1-(((R )-第三丁基亞磺醯基)胺基)乙基)噻吩-2-基)-6-氟苯甲基)(甲基)胺甲酸第三丁酯（84.0 g，152 mmol，85%純度）。LCMS [M-100]⁺ : 369.1。Step D: Under nitrogen atmosphere, to (2-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl ) (Methyl) tertiary butyl carbamate (80.0 g, 160 mmol, 73% purity, 1.00 equivalent) and ( R ) -N -[(1 R )-1-(5-bromo-2-thienyl) Ethyl]-2-methyl-propane-2-sulfinamide (56.0 g, 180 mmol, 1.13 equivalents) in two

Add cesium carbonate (150 g, 460 mmol, 2.88 equivalents) and Pd(PPh ₃ ) ₄ (20.0 g, 17.3 mmol, 0.10 equivalents) to a solution in alkane (500 mL) and water (100 mL), and place the mixture in Stir at 100°C for 3 hours under a nitrogen atmosphere. The mixture was diluted with water (500 mL), extracted with ethyl acetate (1.00 L×2), the organic phase was washed with brine (200 mL), dried over sodium sulfate, filtered and concentrated in vacuo to obtain a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=0/1 to 5/1) to obtain (2-(5-(( R )-1-) as a yellow oil ((( R )-tert-butylsulfinyl)amino)ethyl)thiophen-2-yl)-6-fluorobenzyl)(methyl)carbamic acid tert-butyl ester (84.0 g, 152 mmol, 85% purity). LCMS [M-100] ⁺ : 369.1.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 7.44-7.36 (m, 1H), 7.27-7.17 (m, 2H), 7.08 (br d, J = 2.8 Hz, 1H), 6.96 (d, J = 3.6 Hz, 1H), 5.88 (br d, J = 6.8 Hz, 1H), 4.65 (quin, J = 6.4 Hz, 1H), 4.56 (s, 2H), 2.48 (s, 3H), 1.55 (br d , J = 6.8 Hz, 3H), 1.33 (br s, 9H), 1.13 (s, 9H).

Step E: To (2-(5-(( R )-1-((( R )-tertiary butylsulfinyl)amino)ethyl)thiophen-2-yl)-6-fluorobenzyl (Methyl) tertiary butyl carbamate (80.0 g, 145 mmol, 85% purity, 1.00 equivalent) in THF (240 mL) and water (48.0 mL), add iodine (6.80 g, 26.8 mmol) , 0.19 equivalent). The reaction was heated at 50°C for 2 hours, then diluted with water (500 mL), and extracted with ethyl acetate (500 mL×2). The organic phase was washed with brine (200 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to give a residue. The residue was purified (SiO _2, dichloromethane / methanol = 300/1 to 10/1) was purified by column chromatography to give a yellow oil of (R) - (2- (5- (1- amine (Ethyl)thiophen-2-yl)-6-fluorobenzyl)(methyl)carbamate (40.0 g, 110 mmol). LCMS [M-16] ⁺ : 348.1. Intermediate T

烷（50.0 mL）中之混合物中添加三丁基(1-乙氧基乙烯基)錫（5.00 g，13.8 mmol，4.67 mL，1.53當量），且將混合物在氮氣氛圍下在80℃下攪拌12小時。隨後向該混合物中添加飽和氟化鉀溶液（100 mL），且將該溶液在20℃下攪拌1小時。將混合物用乙酸乙酯（100 mL×3）萃取，且將合併之有機相用鹽水（100 mL×3）洗滌，經無水硫酸鈉乾燥，過濾，且在減壓下濃縮，得到粗製的呈黃色油狀之1-(苯甲氧基)-3-(1-乙氧基乙烯基)-5-(三氟甲基)苯（2.90 g，粗製）。該粗製油無需進一步純化即可用於下一步。Step A: At 20°C, add 1-(benzyloxy)-3-bromo-5-(trifluoromethyl)benzene (3.00 g, 9.06 mmol, 1.00 equivalent) and Pd(dppf)Cl2 (663 mg , 906 µmol, 0.10 equivalent) in two

Tributyl(1-ethoxyvinyl)tin (5.00 g, 13.8 mmol, 4.67 mL, 1.53 equivalents) was added to the mixture in alkane (50.0 mL), and the mixture was stirred at 80°C under a nitrogen atmosphere. Hour. Then a saturated potassium fluoride solution (100 mL) was added to the mixture, and the solution was stirred at 20°C for 1 hour. The mixture was extracted with ethyl acetate (100 mL×3), and the combined organic phase was washed with brine (100 mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude yellow Oily 1-(benzyloxy)-3-(1-ethoxyvinyl)-5-(trifluoromethyl)benzene (2.90 g, crude). The crude oil can be used in the next step without further purification.

Step B: Add 1-(benzyloxy)-3-(1-ethoxyvinyl)-5-(trifluoromethyl)benzene (2.90 g, 9.00 mmol, crude, 1.00 equivalent) in tetrahydrofuran (30.0 mL) was added hydrochloric acid (3.0 M in THF, 10.0 mL, 3.33 equivalents), and the solution was stirred at 20°C for 1 hour. The mixture was then diluted with water (60.0 mL), extracted with ethyl acetate (20.0 mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate = 50/1 to 10/1) to obtain 1-(3-(benzyloxy)-5- (Trifluoromethyl)phenyl)ethan-1-one (2.60 g, 8.84 mmol, 98.2% yield).

¹ H NMR (400 MHz, CDCl ₃ ) δ = 7.79 (s, 1H), 7.74 (s, 1H), 7.45-7.39 (m, 6H), 5.16 (s, 2H), 2.63 (s, 3H).

Step C: Under nitrogen atmosphere, add 1-(3-(benzyloxy)-5-(trifluoromethyl)phenyl)ethan-1-one (2.60g, 8.84mmol, 1.00 equivalent) and ( R )-2-Methylpropane-2-sulfinamide (1.39 g, 11.5 mmol, 1.30 equivalents) in tetrahydrofuran (40.0 mL) was added titanium (IV) ethoxide (5.02 g, 17.7 mmol, 5.22 mL, 2.00 equivalents), and the solution was stirred at 70°C for 12 hours. The mixture was then concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate = 20/1 to 10/1) to obtain ( R )- as a yellow oil N -(1-(3-(Benzyloxy)-5-(trifluoromethyl)phenyl)ethylene)-2-methylpropane-2-sulfinamide (2.20 g, 5.03 mmol, 57.0% yield).

¹ H NMR (400 MHz, CDCl3) δ = 7.45 (d, J = 10.0 Hz, 2H), 7.24-7.13 (m, 6H), 4.94 (s, 2H), 2.56 (s, 3H), 1.10 (s, 9H).

Step D: To ( R ) -N -(1-(3-(benzyloxy)-5-(trifluoromethyl)phenyl)ethylene)-2-methylpropane- A mixture of 2-sulfinamide (2.20 g, 5.54 mmol, 1.00 equivalent) in tetrahydrofuran (30.0 mL) was added sodium borohydride (270 mg, 7.14 mmol, 1.29 equivalent), and the mixture was stirred at 20°C for 3 hours . To the mixture was added saturated aqueous ammonium chloride solution (80.0 mL), and the resulting mixture was stirred at 20°C for 30 minutes. The mixture was then extracted with ethyl acetate (80.0 mL×3), and the combined organic phase was washed with brine (80.0 mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 50/1 to 3/1) to obtain ( R ) -N -(( R )-1-(3) as a yellow oil -(Benzyloxy)-5-(trifluoromethyl)phenyl)ethyl)-2-methylpropane-2-sulfinamide (1.20 g, 3.00 mmol, 54.3% yield).

¹ H NMR (400 MHz, CDCl ₃ ) δ = 7.53-7.32 (m, 5H), 7.23-7.12 (m, 3H), 5.12 (s, 2H), 4.62-4.53 (m, 1H), 3.43 (d, J = 2.8 Hz, 1H), 1.53 (d, J = 6.4 Hz, 3H), 1.25 (s, 9H).

烷中，751 µL，1.00當量），且將該溶液在20℃下攪拌20分鐘。將混合物在減壓下濃縮以移除，得到呈白色固體狀之(R)-1-(3-(苯甲氧基)-5-(三氟甲基)苯基)乙-1-胺（1.20 g，粗製，HCl），其無需進一步純化即可使用。Step E: To ( R ) -N -(( R )-1-(3-(benzyloxy)-5-(trifluoromethyl)phenyl)ethyl)-2-methylpropane-2- Sulfonamide (1.20 g, 3.00 mmol, 1.00 equivalent) solution was added hydrochloric acid (4.0M in two

In alkane, 751 µL, 1.00 equivalent), and the solution was stirred at 20°C for 20 minutes. The mixture was concentrated under reduced pressure for removal to obtain (R)-1-(3-(benzyloxy)-5-(trifluoromethyl)phenyl)ethan-1-amine ( 1.20 g, crude, HCl), which can be used without further purification.

¹ H NMR (400 MHz, CDCl ₃ ) δ = 8.82 (s, 2H), 7.44-7.31 (m, 8H), 5.09 (s, 2H), 4.42 (s, 1H), 1.43 (s, 3H). Intermediate U

Step A: To a solution of 3-acetyl-5-fluorobenzonitrile (2.00 g, 12.3 mmol, 1.00 equivalent) in tetrahydrofuran (20.0 mL) was added titanium ethoxide (5.59 g, 24.5 mmol, 5.08 mL, 2.00 Equivalent) and ( R )-2-methylpropane-2-sulfinamide (1.93 g, 15.9 mmol, 1.30 equivalent). The mixture was degassed and flushed with nitrogen 3 times, and then stirred at 70°C for 12 hours under a nitrogen atmosphere. The mixture was diluted with water (20.0 mL) and filtered. The filtrate was extracted with ethyl acetate (30.0 mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 50/1 to 1/1) to obtain ( R , E ) -N -(1-(3) as a yellow oil -Cyano-5-fluorophenyl)ethylene)-2-methylpropane-2-sulfinamide (1.01 g, 3.68 mmol, 30.0% yield, 97.5% purity). LCMS [M+1] ⁺ : 267.1.

¹ H NMR (400 MHz, CDCl ₃ ) δ = 7.93 (s, 1H), 7.82-7.79 (m, 1H), 7.45-7.52 (m, 1H), 2.79 (s, 3H), 1.35 (s, 9H) .

Step B: To ( R , E ) -N -(1-(3-cyano-5-fluorophenyl)ethylene)-2-methylpropane-2-sulfinamide ( To a solution of 900 mg, 3.38 mmol, 1.00 equivalent) in tetrahydrofuran (10.0 mL), add sodium borohydride (383 mg, 10.1 mmol, 3.00 equivalent). The mixture was then warmed to 20°C and stirred for 2 hours. At 25°C, the mixture was quenched with saturated aqueous ammonium chloride solution (20.0 mL), extracted with ethyl acetate (20.0 mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue . The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 20/1 to 0/1) to obtain ( R ) -N -(( R )-1-(3-cyano group) -5-fluorophenyl)ethyl)-2-methylpropane-2-sulfinamide (711 mg, 2.52 mmol, 74.5% yield, 95.3% purity). LCMS [M+1] ⁺ : 269.1.

¹ H NMR (400 MHz, CDCl ₃ ) δ = 7.46 (t, J = 1.2 Hz, 1H), 7.46-7.33 (m, 1H), 7.31-7.29 (m, 1H), 4.60-4.55 (m, 1H) , 3.47 (d, J = 3.6 Hz, 1 H), 1.54 (d, J = 6.8 Hz, 3 H), 1.25 (s, 9 H).

烷（3.00 mL）中之溶液中添加鹽酸於乙酸乙酯溶液（4.0 M，9.94 mL，15.0當量）。將混合物在20℃下攪拌2小時。將混合物用飽和碳酸氫鈉溶液（10.0 mL）中和，用乙酸乙酯（10.0 mL×3）萃取，經無水硫酸鈉乾燥，過濾，且在減壓下濃縮，得到呈黃色油狀之(R)-3-(1-胺基乙基)-5-氟苯甲腈（330 mg，粗製）。Step C: To ( R ) -N -(( R )-1-(3-cyano-5-fluorophenyl)ethyl)-2-methylpropane-2-sulfinamide (711 mg, 2.65 mmol, 1.00 equivalent) in two

Add hydrochloric acid in ethyl acetate solution (4.0 M, 9.94 mL, 15.0 equivalents) to the solution in alkane (3.00 mL). The mixture was stirred at 20°C for 2 hours. The mixture was neutralized with saturated sodium bicarbonate solution (10.0 mL), extracted with ethyl acetate (10.0 mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain (R )-3-(1-aminoethyl)-5-fluorobenzonitrile (330 mg, crude).

¹ H NMR (400 MHz, CD ₃ OD) δ = 7.72-7.71 (m, 1 H), 7.67-7.66 (m, 1 H), 7.65-7.62 (m, 1 H), 4.59 (q, J = 6.8 Hz, 1 H), 1.65 (d, J = 6.8 Hz, 3 H). Intermediate V

Step A: Add ice-cold concentrated sulfuric acid (100 mL) to 1-bromo-2-methyl-3-(trifluoromethyl)benzene (10.0 g, 41.8 mmol, 1.00 equivalent) at 0°C, and then Potassium nitrate (12.7 g, 125 mmol, 3.00 equivalents) was slowly added, and then the mixture was stirred at 100°C for 1 hour. The mixture was then cooled to 25°C, poured into ice water (500 mL), and extracted with ethyl acetate (300 mL×3). The combined organic layer was washed with brine (400 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 1/0 to 1/1) to obtain 1-bromo-2-methyl-5-nitro as a white oil -3-(Trifluoromethyl)benzene (5.20 g, 16.9 mmol, 40.4% yield).

¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 8.72 (d, J = 2.0 Hz, 1H), 8.40 (d, J = 2.4 Hz, 1H), 2.58-2.62 (m, 3H).

烷（60.0 mL）中之混合物脫氣且用氮氣沖洗3次，且隨後將混合物在氮氣氛圍下在80℃下攪拌10小時。將反應混合物用飽和氟化鉀溶液（300 mL）淬滅，且在25℃下攪拌2小時。隨後將懸浮液用乙酸乙酯（180 mL×3）萃取。將合併之有機層用鹽水（200 mL×3）洗滌，經硫酸鈉乾燥，過濾，且在減壓下濃縮，得到呈黑色油狀之1-(1-乙氧基乙烯基)-2-甲基-5-硝基-3-(三氟甲基)苯（6.00 g，粗製）。Step B: Combine 1-bromo-2-methyl-5-nitro-3-(trifluoromethyl)benzene (5.20 g, 18.3 mmol, 1.00 equivalent), tributyl (1-ethoxyvinyl) Tin (8.60 g, 23.8 mmol, 8.03 mL, 1.30 equivalent) and Pd(PPh ₃ ) ₂ Cl ₂ (385 mg, 549 µmol, 0.03 equivalent) in two

The mixture in alkane (60.0 mL) was degassed and flushed with nitrogen 3 times, and then the mixture was stirred at 80°C for 10 hours under a nitrogen atmosphere. The reaction mixture was quenched with saturated potassium fluoride solution (300 mL), and stirred at 25°C for 2 hours. The suspension was then extracted with ethyl acetate (180 mL×3). The combined organic layer was washed with brine (200 mL×3), dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain 1-(1-ethoxyvinyl)-2-methan as a black oil 5-nitro-3-(trifluoromethyl)benzene (6.00 g, crude).

¹ H NMR (400 MHz, CD ₃ OD) δ = 8.47 (d, J = 2.0 Hz, 1H), 8.32 (d, J = 2.0 Hz, 1H), 4.58 (d, J = 2.8 Hz, 1H), 4.32 (d, J = 2.4 Hz, 1H), 4.00-3.95 (m, 2H), 2.56 (d, J = 1.2 Hz, 3H), 1.37 (t, J = 7.0 Hz, 3H).

Step C: Combine 1-(1-ethoxyvinyl)-2-methyl-5-nitro-3-(trifluoromethyl)benzene (6.00 g, 21.8 mmol, 1.00 equivalent) and hydrochloric acid (3.0 M , 20.7 mL, 2.85 equivalents) in THF (80.0 mL) was stirred at 20°C for 1 hour under a nitrogen atmosphere. The reaction mixture was quenched by adding water (100 mL), and then extracted with ethyl acetate (60.0 mL×3). The combined organic layer was washed with brine (70.0 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 1/0 to 10/1) to obtain 1-(2-methyl-5-nitro-) as a yellow oil 3-(Trifluoromethyl)phenyl)ethan-1-one (4.10 g, 16.5 mmol, 76.0% yield).

¹ H NMR (400MHz, CD ₃ OD) δ = 8.67 (s, 1H), 8.57 (s, 1H), 2.66 (s, 3H), 2.60 (s, 3H).

Step D: To 1-(2-methyl-5-nitro-3-(trifluoromethyl)phenyl)ethan-1-one (2.00 g, 8.09 mmol, 1.00 equivalent) and (R)-2- To a solution of methylpropane-2-sulfinamide (1.27 g, 10.5 mmol, 1.30 equivalents) in THF (20.0 mL) was added Ti(OEt) ₄ (3.69 g _, 16.1 mmol, 3.36 mL, 2.00 equivalents), The mixture was stirred at 70°C for 12 hours under a nitrogen atmosphere. The reaction mixture was diluted with water (70.0 mL) and ethyl acetate (60.0 mL), filtered, and extracted with ethyl acetate (50.0 mL×3). The combined organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 1/0 to 5/1) to obtain ( R , E )-2-methyl- N -as a yellow oil (1-(2-Methyl-5-nitro-3-(trifluoromethyl)phenyl)ethylene)propane-2-sulfinamide (2.00 g, 5.71 mmol, 70.5% yield).

¹ H NMR (400 MHz, CD ₃ OD) δ = 8.43 (s, 1H), 8.30 (s, 1H), 2.75 (s, 3H), 2.58 (s, 3H), 1.30 (m, 9H).

Step E: Ethylene to (R , E )-2-methyl- N -(1-(2-methyl-5-nitro-3-(trifluoromethyl)phenyl) at 0°C ) To a solution of propane-2-sulfinamide (2.00 g, 5.71 mmol, 1.00 equivalent) in THF (23.0 mL) was added sodium borohydride (647 mg, 17.1 mmol, 3.00 equivalent). The mixture was then stirred at 20°C for 2 hours, and saturated sodium bicarbonate was added, followed by dilution with water (100 mL). The mixture was extracted with ethyl acetate (60.0 mL×3), and the combined organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 1/0 to 0/1) to obtain ( R )-2-methyl- N -( ( R )-1-(2-Methyl-5-nitro-3-(trifluoromethyl)phenyl)ethyl)propane-2-sulfinamide (700 mg, 1.75 mmol, 30.6% yield ). LCMS [M+1] ⁺ : 353.0.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 8.67 (d, J = 2.4 Hz, 1H), 8.31 (d, J = 2.0 Hz, 1H), 6.09 (d, J = 7.2 Hz, 1H), 4.83-4.79 (m, 1H), 2.54 (s, 3H), 1.43 (d, J = 6.8 Hz, 1H), 1.11 (m, 9H).

Step F: Add ( R )-2-methyl- N -(( R )-1-(2-methyl-5-nitro-3-(trifluoromethyl)phenyl)ethyl)propane-2 -A mixture of sulfinamide (700 mg, 1.99 mmol, 1.00 equivalent) and iodine (151 mg, 595 mmol, 120 µL, 0.30 equivalent) in tetrahydrofuran (8.00 mL) and water (2.00 mL) is degassed and nitrogen is used It was rinsed 3 times, and then the mixture was stirred at 50°C for 2 hours under a nitrogen atmosphere. The reaction was quenched with saturated sodium bicarbonate (50.0 mL), and then extracted with ethyl acetate (30.0 mL×3). The combined organic phase was washed with brine (20.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 10/1 to 0/1) to obtain ( R )-1-(2-methyl-5) as a yellow solid -Nitro-3-(trifluoromethyl)phenyl)ethan-1-amine (250 mg, 1.01 mmol, 50.7% yield).

¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 8.76 (d, J = 2.4 Hz, 1H), 8.30 (d, J = 2.4 Hz, 1H), 4.54-4.49 (m, 1H), 2.57 (s , 3H), 1.46 (d, J = 6.4 Hz, 1H). Intermediate W

Step A: To a solution of 1-(3-chloro-2-methylphenyl)ethan-1-one (1.50 g, 8.90 mmol, 1.00 equivalent) in tetrahydrofuran (30.0 mL) was added titanium ethoxide (6.09 g, 26.7 mmol, 5.53 mL, 3.00 equivalents) and ( R )-2-methylpropane-2-sulfinamide (1.40 g, 11.6 mmol, 1.30 equivalents). The mixture was stirred at 70°C for 10 hours. The reaction mixture was quenched with sodium bicarbonate (50.0 mL) at 20°C, and then stirred for 10 minutes. The solid was filtered, and the filtrate was extracted with ethyl acetate (20.0 mL×3). The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give ( R , E ) -N -(1-(3-chloro-2-methyl) as a yellow oil (Phenyl)ethylene)-2-methylpropane-2-sulfinamide (2.40 g, crude). LCMS [M+1] ⁺ : 272.0.

Step B: To ( R , E ) -N -(1-(3-chloro-2-methylphenyl)ethylene)-2-methylpropane-2-sulfinamide at -40°C (2.30 g, 8.46 mmol, 1.00 equivalent) To a solution in tetrahydrofuran (30.0 mL) was added sodium borohydride (850 mg, 22.5 mmol, 2.66 equivalent), and the mixture was stirred at -40°C for 2 hours. The reaction mixture was quenched with saturated ammonium chloride solution (50.0 mL) at 20°C, and then stirred for 10 minutes. The solid was filtered out, and the filtered material was extracted with ethyl acetate (20.0 mL×3). The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 1/0 to 1/1) to obtain ( R ) -N -(( R )-1- as a colorless oil (3-Chloro-2-methylphenyl)ethyl)-2-methylpropane-2-sulfinamide (1.50 g, 5.48 mmol, 64.7% yield). LCMS [M+1] ⁺ : 274.1.

Step C: At 0℃, to ( R ) -N -(( R )-1-(3-chloro-2-methylphenyl)ethyl)-2-methylpropane-2-sulfinamide (1.10 g, 4.02 mmol, 1.00 equivalent) in ethyl acetate (20.0 mL) was added hydrochloride in ethyl acetate solution (4.0 M, 30.0 mL), and the mixture was stirred at 20°C for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain ( R )-1-(3-chloro-2-methylphenyl)ethan-1-amine (700 mg, crude) as a white solid. LCMS [M+1] ⁺ : 170.1. Intermediate X

Step A: Add 1-(3-methyl-5-(trifluoromethyl)phenyl)ethan-1-one (500 mg, 2.47 mmol, 1.00 equivalent) and ( R )-2-methylpropane-2 _{-Add Ti(OEt) 4} (1.30 g, 5.69 mmol, 1.18 mL, 2.30 equivalents) to a solution of sulfinamide (689 mg, 5.69 mmol, 2.30 equivalents) in THF (7.00 mL), and place the mixture in a nitrogen atmosphere Stir at 70°C for 12 hours. The reaction mixture was diluted with water (30.0 mL) and ethyl acetate (20.0 mL), filtered, and the filtrate was extracted with ethyl acetate (3×20.0 mL). The combined organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 10/1) to obtain ( R , E )-2-methyl- N -(1-( 3-Methyl-5-(trifluoromethyl)phenyl)ethylene)propane-2-sulfinamide (750 mg, 2.46 mmol, 99.3% yield). LCMS [M+1] ⁺ : 306.1.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 7.99 (s, 1H), 7.95 (s, 1H), 7.75 (s, 1H), 5.75 (s, 1H), 2.76 (s, 3H), 2.46 (s, 3H), 1.22 (s, 9H).

Step B: To ( R , E )-2-methyl- N -(1-(3-methyl-5-(trifluoromethyl)phenyl)ethyl)propane-2 at -40°C -Sulfonamide (650 mg, 2.13 mmol, 1.00 equivalent) in THF (15.0 mL) was added with sodium borohydride (253 mg, 6.69 mmol, 3.14 equivalent). The mixture was stirred at -40°C for 2 hours. To the mixture was added saturated sodium bicarbonate solution, and diluted with water (50.0 mL). The mixture was extracted with ethyl acetate (3×50.0 mL), and the combined organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 5/1 to 2/1) to obtain ( R )-2-methyl- N -( ( R )-1-(3-Methyl-5-(trifluoromethyl)phenyl)ethyl)propane-2-sulfinamide (320 mg, 1.04 mmol, 48.9% yield). LCMS [M+1] ⁺ : 308.1.

¹ H NMR (400 MHz, CD ₃ OD) δ = 7.52 (s, 1H), 7.50 (s, 1H), 7.39 (s, 1H), 4.56 -4.51 (m, 1H), 2.44 (s, 1H), 1.54-1.53 (d, 3H), 1.25 (s, 9H).

Step C: Combine the resulting mixture with ( R )-2-methyl- N -(( R )-1-(3-methyl-5-(trifluoromethyl)phenyl)ethyl)propane-2- A solution of sulfinamide (305 mg, 992 µmol, 1.00 equivalent) in hydrochloric acid (4.0 M in ethyl acetate, 10.0 mL) was stirred at 25°C for 1 hour, and concentrated under reduced pressure to obtain a pale yellow solid ( R )-1-(3-methyl-5-(trifluoromethyl)phenyl)ethan-1-amine (200 mg, crude) in the form. The crude product can be used directly in the next step without further purification. LCMS [M+1] ⁺ : 204.0. Intermediate Y

Step A: Add 1-(4-amino-6-(trifluoromethyl)pyridin-2-yl)ethan-1-one (35.6 g, 175 mmol, 1.00 equivalent) and ( R )-2-methyl To a solution of propane-2-sulfinamide (25.4 g, 209 mmol, 1.20 equivalents) in THF (350 mL) was added titanium(IV) isopropoxide (149 g, 524 mmol, 155 mL, 3.00 equivalents) and 1,2-Dimethoxyethane (15.7 g, 175 mmol, 18.1 mL, 1.00 equivalent). The reaction mixture was stirred at 80°C for 12 hours, after which water (50.0 mL) was added to obtain a suspension. The suspension was filtered, and the filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel chromatography (petroleum ether/ethyl acetate = 10/1 to 1/1) to obtain a brown oil ( R ) -N -(1-(4-Amino-6-(trifluoromethyl)pyridin-2-yl)ethyl)-2-methylpropane-2-sulfinamide (44.0 g, 143 mmol, 82.0% yield).

¹ H NMR (400 MHz, CDCl ₃ ) δ = 7.45 (d, J = 2.0 Hz, 1H), 6.97 (d, J = 2.0 Hz, 1H), 4.56 (br s, 2H), 2.82 (s, 3H) , 1.33 (s, 9H).

Step B: At 0 ℃, to ( R ) -N -(1-(4-amino-6-(trifluoromethyl)pyridin-2-yl)ethylene)-2-methylpropane-2 -Sulfonamide (44.0 g, 143 mmol, 1.00 equivalent) in THF (400 mL) was added portionwise sodium borohydride (16.3 g, 430 mmol, 3.00 equivalent), then the reaction was stirred at 0°C 1 hour. The mixture was slowly poured into water (200 mL) and stirred for 5 minutes, then extracted with ethyl acetate (300×3 mL). The combined organic phase was washed with brine (200×3 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 10/1 to 1/1) to obtain ( R ) -N -(( R )-1- (4-Amino-6-(trifluoromethyl)pyridin-2-yl)ethyl)-2-methylpropane-2-sulfinamide (24.0 g, 76.2 mmol, 53.2% yield, 98.2% purity).

¹ H NMR (400 MHz, CDCl ₃ ) δ = 6.63 (d, J = 2.0 Hz, 1H), 6.56 (d, J = 2.0 Hz, 1H), 5.06 (d, J = 6.0 Hz, 1H), 4.69 ( s, 2H), 4.46-4.39 (m, 1H), 1.45 (d, J = 6.8 Hz, 3H), 1.27 (s, 9H).

烷（200 mL）中之溶液在25℃下攪拌2小時。過濾混合物，且用乙酸乙酯（100 mL）洗滌濾餅，隨後將濾餅收集且在真空下乾燥，得到呈白色固體狀之(R )-2-(1-胺基乙基)-6-(三氟甲基)吡啶-4-胺（鹽酸鹽）。Step C: Add ( R ) -N -(( R )-1-(4-amino-6-(trifluoromethyl)pyridin-2-yl)ethyl)-2-methylpropane-2-ylidene Sulfonamide (23.5 g, 76.0 mmol, 1.00 equivalent) in HCl/two

The solution in alkane (200 mL) was stirred at 25°C for 2 hours. The mixture was filtered, and the filter cake was washed with ethyl acetate (100 mL), then the filter cake was collected and dried under vacuum to give ( R )-2-(1-aminoethyl)-6- as a white solid (Trifluoromethyl)pyridine-4-amine (hydrochloride).

¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 8.43 (br s, 3H), 6.93 (br d, J = 2.0 Hz, 2H), 6.74 (d, J = 1.6 Hz, 1H), 4.34-4.27 (m, 1H), 1.45 (d, J = 6.8 Hz, 3H). Intermediate Z

Step A: To 1-(2-methylpyridin-3-yl)ethan-1-one (800 mg, 5.92 mmol, 1.00 equivalent) and ( S )-2-methylpropane-2-sulfinamide ( To a solution of 933 mg, 7.69 mmol, 1.30 equivalents) in tetrahydrofuran (8.00 mL) was added titanium (IV) ethoxide (2.70 g, 11.8 mmol, 2.45 mL, 2.00 equivalents) and 1,2-dimethoxyethane ( 533 mg, 5.92 mmol, 615 µL, 1.00 equivalent), and the mixture was stirred at 70°C for 16 hours. After cooling to 25°C, the mixture was concentrated under reduced pressure and _{purified by column chromatography (SiO 2} , petroleum ether/ethyl acetate = 5/1 to 1/1) to obtain ( S )-2-Methyl- N- (1-(2-methylpyridin-3-yl)ethylene)propane-2-sulfinamide (1.25 g, 5.24 mmol, 88.6% yield). LCMS [M+1] ⁺ : 239.2.

Step B: To ( S )-2-methyl- N -(1-(2-methylpyridin-3-yl)ethyl)propane-2-sulfinamide (1.25 g , 5.24 mmol, 1.00 equiv) in tetrahydrofuran (7.00 mL) was added dropwise lithium tri-second butyl borohydride (1.0 M in THF, 7.87 mL, 1.50 equiv) for 30 minutes, then at -78°C Stir for another hour. The reaction mixture was then quenched by adding saturated ammonium chloride solution (in water, 30.0 mL) at 0°C, and stirred at 25°C for another 1 hour. The solution was then extracted with ethyl acetate (50.0 mL×3), and the combined organic layer was washed with brine (30.0 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified twice by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 5/1 to 0/1) to obtain ( S )-2-methyl- N -as a white solid (( R )-1-(2-methylpyridin-3-yl)ethyl)propane-2-sulfinamide (600 mg, 2.50 mmol, 47.6% yield). LCMS [M+1] ⁺ : 432.3.

¹ H NMR (400 MHz, CDCl ₃ ) δ = 8.36 (dd, J =1.2, 3.6 Hz, 1H), 7.64 (dd, J =1.6, 8.0 Hz, 1H), 7.12 (dd, J =4.8, 7.6 Hz , 1H), 4.81-4.70 (m, 1H), 2.58 (s, 3H), 1.47 (d, J =6.8 Hz, 3H), 1.14 (s, 9H).

SFC conditions: column: Chiralpak AD-3 50×4.6 mm inner diameter, 3 um; mobile phase: phase A: CO ₂ , phase B: MeOH (0.05% diethylamine); gradient dissolution: MeOH (0.05% diethyl) Amine) in 5% to 40% CO2; flow rate: 3 ml/min; detector: PDA; column temperature: 35°C; back pressure: 100 Bar.

烷（3.00mL）中之混合物在氮氣氛圍下在0℃下攪拌30分鐘。在此時間後，形成白色沈澱物，且將懸浮液過濾。將濾餅收集且在真空下乾燥，且將殘餘物藉由製備型HPLC[管柱：Waters Xbridge 150×25 mm×5 um；移動相：A相：水（0.05%氫氧化銨v/v），B相：MeCN；B%：3%-33%]進一步純化，得到呈無色油狀之(R )-1-(2-甲基吡啶-3-基)乙-1-胺（370 mg，2.23 mmol，89.2%產率，82%純度）。LCMS [M-16]⁺ : 120.3。 中間物AA

Step C: Add ( S )-2-methyl- N -(( R )-1-(2-methylpyridin-3-yl)ethyl)propane-2-sulfinamide (600 mg, 2.50 mmol , 1.00 equivalent) in HCl·two

The mixture in alkane (3.00 mL) was stirred at 0°C for 30 minutes under a nitrogen atmosphere. After this time, a white precipitate formed and the suspension was filtered. The filter cake was collected and dried under vacuum, and the residue was subjected to preparative HPLC [column: Waters Xbridge 150×25 mm×5 um; mobile phase: phase A: water (0.05% ammonium hydroxide v/v) , Phase B: MeCN; B%: 3%-33%] was further purified to obtain ( R )-1-(2-methylpyridin-3-yl)ethan-1-amine (370 mg, 2.23 mmol, 89.2% yield, 82% purity). LCMS [M-16] ⁺ : 120.3. Intermediate AA

烷（50.0 mL）中之溶液中添加PdCl₂ (PPh₃ )₂ （1.40 g，2.00 mmol，0.10當量）及三丁基(1-乙氧基乙烯基)錫（21.7 g，60.0 mmol，20.3 mL，3.00當量），且將該混合物脫氣且用氮氣沖洗（3次），隨後在氮氣氛圍下在100℃下攪拌3小時。將混合物冷卻至室溫，在減壓下濃縮，且將添加的氟化鉀水溶液（2.0 M，100 mL）添加至殘餘物中。將混合物用乙酸乙酯（100 mL×3）萃取，經無水硫酸鈉乾燥且過濾。在減壓下濃縮濾液，得到呈褐色油狀之1-(二氟甲基)-3-(1-乙氧基乙烯基)-2-氟苯（7.50g，粗製），其無需進一步純化即可使用。Step A: Add 1-bromo-3-(difluoromethyl)-2-fluorobenzene (commercially available, 4.50 g, 20.0 mmol, 1.00 equivalent) to 1,4-bis

_{Add PdCl 2} (PPh ₃ ) ₂ (1.40 g, 2.00 mmol, 0.10 equivalent) and tributyl(1-ethoxyvinyl) tin (21.7 g, 60.0 mmol, 20.3 mL) to the solution in alkane (50.0 mL) , 3.00 equivalents), and the mixture was degassed and flushed with nitrogen (3 times), followed by stirring at 100° C. for 3 hours under a nitrogen atmosphere. The mixture was cooled to room temperature, concentrated under reduced pressure, and an aqueous potassium fluoride solution (2.0 M, 100 mL) was added to the residue. The mixture was extracted with ethyl acetate (100 mL×3), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain 1-(difluoromethyl)-3-(1-ethoxyvinyl)-2-fluorobenzene (7.50 g, crude) as a brown oil, which did not require further purification. be usable.

Step B: Add to a solution of 1-(difluoromethyl)-3-(1-ethoxyvinyl)-2-fluorobenzene (7.50 g, 34.7 mmol, 1.00 equivalent) in tetrahydrofuran (50.0 mL) Aqueous hydrochloric acid (30.0 mL, 10% purity), and the mixture was stirred at 25°C for 1 hour. After this time, the pH of the mixture was adjusted to pH~6-8 with aqueous sodium bicarbonate solution, and the mixture was extracted with ethyl acetate (100 mL×3). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate = 1/0 to 5/1) to obtain 1-(3-(difluoromethyl)-2- Fluorophenyl)ethan-1-one (6.01 g, 31.3 mmol, 90.2% yield, 98.0% purity). LCMS [M+1] ⁺ : 189.1.

¹ H NMR (400 MHz, CDCl ₃ ) δ = 8.02-7.97 (m, 1H), 7.80-7.76 (m, 1H), 7.34 (t, J = 8.0 Hz, 1H), 6.94 (t, J = 14.8 Hz , 1H), 2.66 (d, J = 5.2 Hz, 3H).

Step C: Combine ( S )-2-methylpropane-2-sulfinamide (2.32 g, 19.1 mmol, 1.20 equivalents), 1-(3-(difluoromethyl)-2-fluorophenyl)ethyl The mixture of -1-one (3.00 g, 16.0 mmol, 1.00 equivalent) and titanium (IV) ethoxide (7.27 g, 31.9 mmol, 6.60 mL, 2.00 equivalent) in 2-methyltetrahydrofuran (30.0 mL) was degassed and used Nitrogen flushing (3 times), and then stirring at 75°C for 4 hours under a nitrogen atmosphere. The reaction mixture was then cooled, diluted with water (50.0 mL), extracted with ethyl acetate (50.0 mL×3), and the combined organic layer was washed with brine (100 mL×2), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 20/1 to 1/1) to obtain ( S ) -N -(1-(3) -(Difluoromethyl)-2-fluorophenyl)ethylene)-2-methylpropane-2-sulfinamide (1.80 g, 6.18 mmol, 38.8% yield). LCMS [M+1] ⁺ : 292.2.

Step D: To ( S ) -N -(1-(3-(difluoromethyl)-2-fluorophenyl)ethylene)-2-methylpropane- To a solution of 2-sulfinamide (1.80 g, 6.18 mmol, 1.00 equivalent) in 2-methyltetrahydrofuran (30.0 mL) was added lithium tri-second butyl borohydride (3.52 g, 18.5 mmol, 4.10 mL, 3.00 Equivalent), and then the mixture was stirred at -78°C for 3 hours under a nitrogen atmosphere. After this time, additional lithium tri-second butyl borohydride (1.76 g, 9.30 mmol, 2.00 mL, 1.50 equivalents) was added, and the solution was degassed and flushed with nitrogen (3 times), and under a nitrogen atmosphere Stir at -78°C for 9 hours. The mixture was cooled to room temperature, diluted with water (30.0 mL), and extracted with ethyl acetate (30.0 mL×3). The combined organic layer was washed with brine (30.0 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate = 20/1 to 1/1) to obtain ( S ) -N -(( R )-1-( 3-(Difluoromethyl)-2-fluorophenyl)ethyl)-2-methylpropane-2-sulfinamide (1.30 g, 4.34 mmol, 70.3% yield, 98% purity). LCMS [M+1] ⁺ : 294.2.

烷中，15.0 mL，14.0當量），且將混合物在25℃下攪拌30分鐘。隨後將混合物用水（30.0 mL）稀釋，用乙酸乙酯（30.0 mL×3）萃取，且將合併之有機層用鹽水（30.0 mL×2）洗滌，經無水硫酸鈉乾燥且過濾。將濾液在減壓下濃縮，得到呈黃色油狀之(R )-1-(3-(二氟甲基)-2-氟苯基)乙-1-胺（480 mg，2.13 mmol，48.0%產率，HCl鹽），其無需進一步純化即可使用。Step E: To ( S ) -N -(( R )-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-methylpropane-2-sulfinamide ( 1.29 g, 4.43 mmol, 1.00 equivalent) was added hydrochloric acid (4.00 M in 1,4-di

In alkane, 15.0 mL, 14.0 equivalents), and the mixture was stirred at 25°C for 30 minutes. The mixture was then diluted with water (30.0 mL), extracted with ethyl acetate (30.0 mL×3), and the combined organic layer was washed with brine (30.0 mL×2), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain ( R )-1-(3-(difluoromethyl)-2-fluorophenyl)ethan-1-amine (480 mg, 2.13 mmol, 48.0%) as a yellow oil Yield, HCl salt), which can be used without further purification.

¹ H NMR (400 MHz, CDCl ₃ ) δ = 7.52-7.47 (m, 2H), 7.24-7.19 (m, 1H), 6.88 (t, J = 14.8 Hz, 1H), 4.85-4.92 (m, 1H) , 1.57 (d, J = 6.8 Hz, 3H).

（339 mg，1.59 mmol，1.00當量）及氟化鉀（461 mg，7.93 mmol，186 µL，5.00當量）於二甲基亞碸（6.00 mL）中之混合物脫氣且用氮氣沖洗（3次），且將混合物在氮氣氛圍下在130℃下攪拌12小時。隨後將混合物冷卻至25℃，用水（30.0 mL）稀釋，且用乙酸乙酯（30.0 mL×3）萃取。將合併之有機層用鹽水（30.0 mL×3）洗滌，經硫酸鈉乾燥，過濾，且在減壓下濃縮。將殘餘物藉由管柱層析法（矽膠，石油醚/乙酸乙酯＝10/1至1/1）及製備型HPLC[管柱：Phenomenex luna C18 150×25 mm×10 um；移動相：A相：水（0.225%甲酸），B相：乙腈；B%：20%-50%]純化，得到呈黃色固體狀之(R )-7-氯-N -(1-(3-(二氟甲基)-2-氟苯基)乙基)-4-甲基吡啶并[3,4-d ]嗒

-1-胺（250 mg，629 µmol，39.7%產率，92.3%純度）。LCMS [M+1]⁺ : 367.2。 中間物AB

Step F: Combine ( R )-1-(3-(difluoromethyl)-2-fluorophenyl)ethan-1-amine (300 mg, 1.59 mmol, 1.00 equivalent), 1,7-dichloro-4 -Methylpyrido[3,4-d]ta

The mixture of (339 mg, 1.59 mmol, 1.00 equivalent) and potassium fluoride (461 mg, 7.93 mmol, 186 µL, 5.00 equivalent) in dimethyl sulfoxide (6.00 mL) was degassed and flushed with nitrogen (3 times) , And the mixture was stirred at 130°C for 12 hours under a nitrogen atmosphere. The mixture was then cooled to 25°C, diluted with water (30.0 mL), and extracted with ethyl acetate (30.0 mL×3). The combined organic layer was washed with brine (30.0 mL×3), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to column chromatography (silica gel, petroleum ether/ethyl acetate = 10/1 to 1/1) and preparative HPLC [column: Phenomenex luna C18 150×25 mm×10 um; mobile phase: Phase A: water (0.225% formic acid), phase B: acetonitrile; B%: 20%-50%] purified to obtain ( R )-7-chloro- N -(1-(3-(二) as a yellow solid (Fluoromethyl)-2-fluorophenyl)ethyl)-4-methylpyrido[3,4- d ]

-1-amine (250 mg, 629 µmol, 39.7% yield, 92.3% purity). LCMS [M+1] ⁺ : 367.2. Intermediate AB

Step A: To 3-bromo-5-fluoro-2-methylbenzoic acid (4.00 g, 17.2 mmol, 1.00 equivalent) and N,O -dimethylhydroxylamine (1.84 g, 18.9 mmol, 1.10 equivalent, HCl salt) Add N,N -diisopropylethylamine (6.66 g, 51.5 mmol, 8.97 mL, 3.00 equivalents) and HATU (7.83 g, 20.6 mmol, 1.20 equivalents) to the solution in DMF (50.0 mL), and react The mixture was stirred at 20°C for 2 hours. The reaction mixture was diluted with ethyl acetate (50.0 mL), washed with brine (30.0 mL×3), and the combined organic phases were collected, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 5/1 to 2/1) to obtain 3-bromo-5-fluoro- N -methoxy as a white solid -N ,2-Dimethylbenzamide (4.70 g, 17.0 mmol, 99.2% yield).

Step B: Add 3-bromo-5-fluoro- N -methoxy- N ,2-dimethyl-benzamide (4.70 g, 17.0 mmol, 1.00 equivalent) in THF (100 mL Add methylmagnesium bromide (3.0 M, 34.1 mL, 6.00 equivalents) to the solution in) dropwise. After completion of the dropwise addition, the reaction mixture was warmed to 45°C and stirred for 5 hours. The mixture was then cooled to 25°C, quenched with water (20.0 mL), and extracted with ethyl acetate (50.0 mL×3). The combined organic phases were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 5/1) to obtain 1-(3-bromo-5-fluoro-2-methylbenzene as a pale yellow solid) Yl)ethan-1-one (3.80 g, 16.5 mmol, 96.6% yield).

¹ H NMR (400 MHz, CDCl ₃ ) δ = 7.43 (dd, J = 2.8, 7.6 Hz, 1H), 7.19 (dd, J = 2.8, 8.4 Hz, 1H), 2.55 (s, 3H), 2.45 (d , J = 0.4 Hz, 3H).

Step C: Add 1-(3-bromo-5-fluoro-2-methylphenyl)ethan-1-one (3.80 g, 16.5 mmol, 1.00 equivalent) and ( S )-2-methylpropane-2- To a solution of sulfinamide (2.79 g, 23.0 mmol, 1.40 equivalents) in THF (60.0 mL) was added titanium (IV) ethoxide (7.50 g, 32.9 mmol, 6.82 mL, 2.00 equivalents) and 1,2-dimethyl Oxyethane (1.48 g, 16.5 mmol, 1.71 mL, 1.00 equivalent), and the mixture was stirred at 70°C for 12 hours. The reaction mixture was then cooled to 25°C and diluted with ethyl acetate (100 L) and (10.0 L) to obtain a suspension. The suspension was filtered, and the filtrate was concentrated under reduced pressure to remove all volatiles. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 30/1 to 20/1) to obtain ( S ) -N -(1-(3-bromo) as a yellow oil -5-fluoro-2-methylphenyl)ethylene)-2-methylpropane-2-sulfinamide (4.70 g, 14.1 mmol, 85.5% yield). LCMS [M+3] ⁺ : 336.0.

¹ H NMR (400 MHz, CDCl ₃ ) δ = 7.35 (br dd, J = 2.4, 7.6 Hz, 1H), 6.92 (dd, J = 2.4, 8.4 Hz, 1H), 2.66 (s, 3H), 2.37 ( s, 3H), 1.30 (s, 9H).

Step D: To ( S ) -N -(1-(3-bromo-5-fluoro-2-methylphenyl)ethyl)-2-methylpropane-2-sulfinate at -78°C To a solution of amide (5.50 g, 16.5 mmol, 1.00 equivalent) in THF (80.0 mL) was added lithium tri-second butyl borohydride (1.0 M, 24.7 mL, 1.50 equivalent) dropwise, and the reaction mixture was warmed Bring to 0°C and stir for 2 hours. The mixture was then diluted with aqueous ammonium chloride solution (30.0 mL), and the resulting solution was extracted with ethyl acetate (50.0 mL×2). The combined organic phases were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was wet triturated with petroleum ether (20.0 mL), filtered, and the filter cake was dried under vacuum to obtain ( S ) -N -(( R )-1-(3-bromo-5- Fluoro-2-methylphenyl)ethyl)-2-methylpropane-2-sulfinamide (3.20 g, 9.52 mmol, 57.8% yield).

¹ H NMR (400 MHz, CDCl ₃ ) δ = 7.24 (dd, J = 2.4, 7.6 Hz, 1H), 7.10 (dd, J = 2.8, 10.0 Hz, 1H), 4.90-4.82 (m, 1H), 3.30 (br d, J = 2.8 Hz, 1H), 2.42 (s, 3H), 1.48 (d, J = 6.8 Hz, 3H), 1.23 (s, 9H).

Step E: To ( S ) -N -(( R )-1-(3-bromo-5-fluoro-2-methylphenyl)ethyl)-2-methylpropane-2-sulfinamide ( 1.60 g, 4.76 mmol, 1.00 equivalent) was added to a solution of THF (20.0 mL) and water (5.00 mL) with iodine (362 mg, 1.43 mmol, 288 µL, 0.30 equivalent), and the mixture was stirred at 50°C 2 Hour. The mixture was then cooled to 25°C, and the pH was adjusted to pH=7 with aqueous sodium bicarbonate solution. The resulting solution was extracted with DCM (20.0 mL×3), and the combined organic phases were dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain ( R )-1-(3-bromo) as a pale yellow oil -5-fluoro-2-methylphenyl)ethan-1-amine (1.20 g, crude). The crude oil can be used without further purification.

Step F: To a solution of ( R )-1-(3-bromo-5-fluoro-2-methylphenyl)ethan-1-amine (1.20 g, 5.17 mmol, 1.00 equivalent) in THF (20.0 mL) Di-tert-butyl dicarbonate (1.35 g, 6.20 mmol, 1.43 mL, 1.20 equivalents) was added, and the mixture was stirred at 20°C for 3 hours. The mixture was then concentrated under reduced pressure, and the residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 150/1 to 70/1) to obtain ( R ) as a white solid -(1-(3-Bromo-5-fluoro-2-methylphenyl)ethyl) carbamic acid tert-butyl ester (1.45 g, 4.36 mmol, 84.4% yield).

Step G: Combine ( R )-(1-(3-bromo-5-fluoro-2-methylphenyl)ethyl) carbamic acid tert-butyl ester (1.35 g, 4.06 mmol, 1.00 equivalent), zinc cyanide (954 mg, 8.13 mmol, 516 µL, 2.00 equivalent), DPPF (451 mg, 813 µmol, 0.20 equivalent), zinc powder (26.6 mg, 406 µmol, 0.10 equivalent) and Pd ₂ (dba) ₃ (372 mg, 406 The mixture in µmol, 0.10 equivalent) in dimethylacetamide (20.0 mL) was degassed and flushed with nitrogen (3 times), and the mixture was stirred at 120°C for 6 hours under a nitrogen atmosphere. The mixture was then diluted with ethyl acetate (60.0 mL), filtered, and the filtrate was washed with brine (30.0 mL×3), dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 100/1 to 30/1) to obtain ( R )-(1-(3-cyano group) as a pale yellow solid Tertiary butyl-5-fluoro-2-methylphenyl)ethyl)carbamate (1.10 g, 3.95 mmol, 97.3% yield).

Step H: To ( R )-(1-(3-cyano-5-fluoro-2-methylphenyl)ethyl) carbamic acid tert-butyl ester (1.10 g, 3.95 mmol, 1.00 equivalent) in DCM ( To the solution in 5.00 mL) was added TFA (1.88 g, 16.5 mmol, 1.22 mL, 4.18 equivalents), and the mixture was stirred at 20°C for 1 hour. The mixture was then concentrated under reduced pressure, and the residue was adjusted to pH=7 with saturated aqueous sodium bicarbonate solution. The resulting solution was extracted with DCM (50.0 mL), and the organic phase was dried over sodium sulfate and concentrated in vacuo to obtain ( R )-3-(1-aminoethyl)-5-fluoro-2 as a brown oil -Methylbenzonitrile (0.80 g, crude), which can be used without further purification. Intermediate AC

烷（20.0 mL）中之溶液中添加PdCl₂ (PPh₃ )₂ （544 mg，775 µmol，0.10當量），且將混合物在80℃下攪拌12小時。隨後將反應混合物冷卻至25℃，用氟化鉀水溶液（100 mL） 稀釋，且隨後用乙酸乙酯（100 mL×3）萃取。將合併之有機層用鹽水（100 mL）洗滌，經硫酸鈉乾燥，過濾，且在減壓下濃縮，得到呈黃色油狀之化合物2-(1-乙氧基乙烯基)-4-氟-6-(三氟甲基)苯胺（4.00 g，粗製）。向2-(1-乙氧基乙烯基)-4-氟-6-(三氟甲基)苯胺（4.00 g，粗製）於四氫呋喃（50.0 mL）中之溶液中逐滴添加鹽酸水溶液（4.00 M，20.0 mL，1.33當量）。隨後將混合物在25℃下攪拌1小時，用水（100 mL） 稀釋且用乙酸乙酯（300 mL×3）萃取。將合併之有機層用鹽水（200 mL）洗滌，經硫酸鈉乾燥，過濾，且在減壓下濃縮。將殘餘物藉由管柱層析法（石油醚/乙酸乙酯＝30/1至3/1）純化，得到呈黃色固體狀之化合物1-(2-胺基-5-氟-3-(三氟甲基)苯基)乙-1-酮（5.60 g，25.3 mmol，42.0%產率，99.9%純度）。Step A: Under nitrogen atmosphere, add 2-bromo-4-fluoro-6-(trifluoromethyl)aniline (2.00 g, 7.75 mmol, 1.00 equivalent) and tributyl(1-ethoxyvinyl)tin (2.80 g, 7.75 mmol, 2.62 mL, 1.00 equivalent) in two

_{PdCl 2} (PPh ₃ ) ₂ (544 mg, 775 µmol, 0.10 equivalent) was added to the solution in alkane (20.0 mL), and the mixture was stirred at 80°C for 12 hours. The reaction mixture was then cooled to 25°C, diluted with an aqueous potassium fluoride solution (100 mL ) , and then extracted with ethyl acetate (100 mL×3). The combined organic layer was washed with brine (100 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the compound 2-(1-ethoxyvinyl)-4-fluoro- as a yellow oil 6-(Trifluoromethyl)aniline (4.00 g, crude). To a solution of 2-(1-ethoxyvinyl)-4-fluoro-6-(trifluoromethyl)aniline (4.00 g, crude) in tetrahydrofuran (50.0 mL) was added dropwise an aqueous hydrochloric acid solution (4.00 M , 20.0 mL, 1.33 equivalents). The mixture was then stirred at 25°C for 1 hour, diluted with water (100 mL ) and extracted with ethyl acetate (300 mL×3). The combined organic layer was washed with brine (200 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate=30/1 to 3/1) to obtain compound 1-(2-amino-5-fluoro-3-() as a yellow solid Trifluoromethyl)phenyl)ethan-1-one (5.60 g, 25.3 mmol, 42.0% yield, 99.9% purity).

¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 7.99 (d, J = 9.2 Hz, 1H), 7.65-7.61 (m, 1H), 7.33 (s, 2H), 2.59 (s, 3H).

Step B: Add 1-(2-amino-5-fluoro-3-(trifluoromethyl)phenyl)ethan-1-one (5.60 g, 25.3 mmol, 1.00 equivalent) in hydrochloric acid (50.0 mL) and water Add sodium nitrite (2.27 g, 32.9 mmol, 1.30 equivalents) to the solution in (100 mL) in batches, and then add potassium iodide (8.41 g, 50.6 mmol, 2.00 equivalents) to the mixture at 0°C. After the addition was complete, the reaction mixture was stirred at 25°C for 12 hours, then diluted with water (100 mL ) , and extracted with ethyl acetate (200 mL×3). The combined organic layer was washed with sodium sulfite (200 mL×3), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate=50/1 to 10/1) to obtain compound 1-(5-fluoro-2-iodo-3-(three) as a yellow solid Fluoromethyl)phenyl)ethan-1-one (5.60 g, 10.3 mmol, 40.8% yield, 61.2% purity).

¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 7.83-7.76 (m, 1H), 7.74-7.71 (m, 1H), 2.56 (s, 3H).

烷（20.0 mL）中之溶液中添加Pd(dppf)Cl₂ （400 mg，542 µmol，0.05當量）及碳酸鉀（7.49 g，54.2 mmol，5.00當量），且將混合物在90℃下攪拌12小時。隨後將混合物冷卻至25℃，用水（50.0 mL） 稀釋且用乙酸乙酯（100 mL×3）萃取。將合併之有機層用鹽水（100 mL）洗滌，經硫酸鈉乾燥，過濾，且在減壓下濃縮。將殘餘物藉由管柱層析法純化（石油醚/乙酸乙酯＝50/1至10/1），得到呈黃色油狀之化合物1-(5-氟-2-甲基-3-(三氟甲基)苯基)乙-1-酮（1.70 g，7.72 mmol，71.2%產率）。Step C: Under a nitrogen atmosphere, add methylboronic acid (1.62 g, 27.1 mmol, 2.50 equivalents) and 1-(5-fluoro-2-iodo-3-(trifluoromethyl)phenyl)ethan-1-one (3.60 g, 10.8 mmol, 1.00 equivalent) in two

_{Pd(dppf)Cl 2} (400 mg, 542 µmol, 0.05 equivalent) and potassium carbonate (7.49 g, 54.2 mmol, 5.00 equivalent) were added to the solution in alkane (20.0 mL), and the mixture was stirred at 90°C for 12 hours . The mixture was then cooled to 25°C, diluted with water (50.0 mL ) and extracted with ethyl acetate (100 mL×3). The combined organic layer was washed with brine (100 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate=50/1 to 10/1) to obtain compound 1-(5-fluoro-2-methyl-3-( Trifluoromethyl)phenyl)ethan-1-one (1.70 g, 7.72 mmol, 71.2% yield).

¹ H NMR (400 MHz, CDCl ₃ ) δ = 7.47 (dd, J = 2.8, 8.8 Hz, 1H), 7.36-7.30 (m, 1H), 2.58 (s, 3H), 2.47 (s, 3H).

Step D: To 1-(5-fluoro-2-methyl-3-(trifluoromethyl)phenyl)ethan-1-one (2.20 g, 9.99 mmol, 1.00 equivalent) and ( R )-2-methyl To a solution of methyl propane-2-sulfinamide (2.42 g, 20.0 mmol, 2.00 equivalents) in tetrahydrofuran (15.0 mL) was added titanium(IV) isopropoxide (5.68 g, 20.0 mmol, 5.90 mL, 2.00 equivalents) And 1-methoxy-2-(2-methoxyethoxy)ethane (4.12 g, 30.7 mmol, 4.40 mL, 3.08 equivalents), and the mixture was stirred at 75°C for 12 hours. The mixture was then cooled to 25°C and diluted with water (50.0 mL) to obtain a suspension. The resulting suspension was filtered, and the filtrate was diluted with ethyl acetate (100 mL×3). The combined organic layer was washed with brine (50.0 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate = 10/1 to 3/1) to obtain the compound ( R ) -N -(1-(5-fluoro-2) as a yellow oil -Methyl-3-(trifluoromethyl)phenyl)ethylene)-2-methylpropane-2-sulfinamide (1.50 g, 4.64 mmol, 46.4% yield).

¹ H NMR (400 MHz, CDCl ₃ ) δ = 7.39 (dd, J = 2.2, 8.8 Hz, 1H), 7.10 (dd, J = 2.4, 8.4 Hz, 1H), 2.68 (s, 3H), 2.41 (s , 3H), 1.30 (s, 9H).

Step E: To ( R ) -N -(1-(5-fluoro-2-methyl-3-(trifluoromethyl)phenyl)ethylene)-2-methylpropane- To a solution of 2-sulfinamide (1.90 g, 5.88 mmol, 1.00 equivalent) in tetrahydrofuran (20.0 mL) was added sodium borohydride (667 mg, 17.6 mmol, 3.00 equivalent) in portions. The reaction mixture was stirred at 0°C for 2 hours, then slowly diluted with saturated aqueous ammonium chloride (50.0 mL) and stirred for 30 minutes. The resulting mixture was extracted with ethyl acetate (100 mL×3), and the combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate = 10/1 to 3/1) to obtain ( R ) -N -(( R )-1-(5-) as a yellow oil Fluoro-2-methyl-3-(trifluoromethyl)phenyl)ethyl)-2-methylpropane-2-sulfinamide (1.30 g, 4.00 mmol, 68.0% yield).

¹ H NMR (400 MHz, CDCl ₃ ) δ = 7.40-7.28 (m, 2H), 4.95-4.84 (m, 1H), 3.40-3.32(m, 1H), 2.43 (s, 3H), 1.49 (d, J = 6.4 Hz, 3H), 1.23 (s, 9H).

烷中，5.00 mL，5.0當量），且將混合物在25℃下攪拌1小時。隨後將混合物在減壓下濃縮，得到呈黃色油狀之化合物(R )-1-(5-氟-2-甲基-3-(三氟甲基)苯基)乙-1-胺（700 mg，2.81 mmol，70.4%產率，88.9純度，HCl鹽），其無需進一步純化即可直接使用。 中間物AD

Step F: To ( R ) -N -(( R )-1-(5-fluoro-2-methyl-3-(trifluoromethyl)phenyl)ethyl)-2-methylpropane-2- Sulfonamide (1.30 g, 4.00 mmol, 1.00 equivalent) in dichloromethane (5.00 mL) was added with hydrochloric acid (4.00 M in 1,4-bis

In alkane, 5.00 mL, 5.0 equivalents), and the mixture was stirred at 25°C for 1 hour. The mixture was then concentrated under reduced pressure to give compound ( R )-1-(5-fluoro-2-methyl-3-(trifluoromethyl)phenyl)ethan-1-amine (700 mg, 2.81 mmol, 70.4% yield, 88.9 purity, HCl salt), which can be used directly without further purification. Intermediate AD

Step A: To 3-bromo-2,5-difluorobenzaldehyde (4.00 g, 18.1 mmol, 1.00 equivalent) and ( R )-2-methylpropane-2-sulfinamide (3.07 g, 25.3 mmol, 1.40 equivalents) to a solution in THF (50.0 mL) was added titanium (IV) ethoxide (8.26 g, 36.2 mmol, 7.51 mL, 2.00 equivalents) and 1,2-dimethoxyethane (1.63 g, 18.1 mmol, 1.88 mL, 1.00 equivalent), and the mixture was stirred at 70°C for 12 hours. The mixture was then cooled to 25°C and slowly diluted with ethyl acetate (50.0 mL) and water (5.00 mL) to obtain a suspension. The suspension was filtered, and the filtrate was concentrated under reduced pressure, and then _{purified by column chromatography (SiO 2} , petroleum ether/ethyl acetate = 20/1 to 10/1) to obtain a white solid ( S) - N - (3- bromo-2,5-phenylene) -2-methyl-2-sulfinyl amine (5.70 g, 17.6 mmol, 97.1 % yield).

¹ H NMR (400 MHz, CDCl ₃ ) δ = 8.81 (d, J = 2.4 Hz, 1H), 7.74 (dd, J = 6.0, 8.4 Hz, 1H), 7.44 (dd, J = 5.2, 8.8 Hz, 1H ), 1.28 (s, 9H).

Step B: Add ( S ) -N -(3-bromo-2,5-difluorobenzyl)-2-methylpropane-2-sulfinamide (5.50 g, 17.0 mmol, 1.00 equiv) in DCM (60.0 mL) was added dropwise methylmagnesium bromide (3.0 M, 17.0 mL, 3.00 equiv), and then the mixture was warmed to 0°C and stirred for 1 hour. The mixture was diluted with aqueous ammonium chloride solution (50.0 mL), and the resulting aqueous solution was extracted with ethyl acetate (50.0 mL×3). The combined organic phases were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 5/1 to 2/1) to obtain ( S ) -N -(( R )-1- as a white solid (3-Bromo-2,5-difluorophenyl)ethyl)-2-methylpropane-2-sulfinamide (3.50 g, 10.3 mmol, 60.6% yield).

¹ H NMR (400 MHz, CDCl ₃ ) δ = 7.31-7.26 (m, 1H), 7.16 (dd, J = 6.4, 8.8 Hz, 1H), 4.89-4.78 (m, 1H), 3.35 (br d, J = 4.0 Hz, 1H), 1.56 (d, J = 6.8 Hz, 3H), 1.23 (s, 9H).

Step C: To ( S ) -N -(( R )-1-(3-bromo-2,5-difluorophenyl)ethyl)-2-methylpropane-2-sulfinamide (1.50 g , 4.41 mmol, 1.00 equivalent) was added to a solution of THF (20.0 mL) and water (5.00 mL) with iodine (336 mg, 1.32 mmol, 266 µL, 0.30 equivalent), and the mixture was stirred at 50°C for 2 hours. The mixture was then cooled to 25°C, and the pH was adjusted to pH=7 with aqueous sodium bicarbonate solution. The resulting aqueous solution was extracted with DCM (20.0 mL×3), and the combined organic phase was dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain ( R )-1-(3-bromo) as a pale yellow oil -2,5-Difluorophenyl)ethan-1-amine (1.20 g, crude). The crude oil can be used directly without further purification.

Step D: Add (R )-1-(3-bromo-2,5-difluorophenyl)ethan-1-amine (1.20 g, 5.08 mmol, 1.00 equivalent) in THF (20.0 mL) Di-tertiary butyl dicarbonate (1.22 g, 5.59 mmol, 1.28 mL, 1.10 equivalents), and the mixture was stirred at 20°C for 2 hours. The reaction mixture was concentrated under reduced pressure and _{purified by column chromatography (SiO 2} , petroleum ether/ethyl acetate=150/1 to 80/1) to obtain ( R )-(1) as a white solid -(3-Bromo-2,5-difluorophenyl)ethyl)carbamate (1.30 g, 3.87 mmol, 76.1% yield).

Step E: Combine ( R )-(1-(3-bromo-2,5-difluorophenyl)ethyl) carbamic acid tert-butyl ester (1.20 g, 3.57 mmol, 1.00 equivalent), zinc cyanide (838 mg, 7.14 mmol, 453 µL, 2.00 equivalent), zinc (23.3 mg, 357 µmol, 0.10 equivalent), DPPF (396 mg, 714 µmol, 0.20 equivalent) and Pd ₂ (dba) ₃ (327 mg, 357 µmol, 0.10 Equivalent) The mixture in dimethylacetamide (20.0 mL) was degassed and flushed with nitrogen (3 times), and the mixture was stirred at 115°C for 3 hours under a nitrogen atmosphere. The mixture was then cooled to 25°C, diluted with ethyl acetate (100 mL), and the organic phase was washed with brine (50.0 mL×3), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 100/1 to 30/1) to obtain ( R )-(1-(3-cyano group) as a pale yellow solid Tertiary butyl-2,5-difluorophenyl)ethyl)carbamate (0.90 g, 3.19 mmol, 89.3% yield).

Step F: To ( R )-(1-(3-cyano-2,5-difluorophenyl)ethyl) carbamic acid tert-butyl ester (0.90 g, 3.19 mmol, 1.00 equivalent) in DCM (10.0 mL TFA (4.62 g, 40.5 mmol, 3.00 mL, 12.7 equivalents) was added to the solution in ), and the reaction mixture was stirred at 20°C for 1 hour. The reaction mixture was then concentrated under reduced pressure, and the residue was diluted with water (10.0 mL). The pH of the solution was adjusted to pH=7 with aqueous sodium bicarbonate, and the resulting aqueous solution was extracted with DCM (20.0 mL×2). The combined organic phase was dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain ( R )-3-(1-aminoethyl)-2,5-difluorobenzonitrile as a pale yellow oil (700 mg, crude). The compound can be used directly without further purification. Intermediate AE

Step A: Add zinc cyanide ( 11.5 g, 176 mmol, 7.56 mL, 1.10 equivalents), and the reaction mixture was stirred at 80°C for 16 hours. The mixture was then cooled to 25°C, diluted with ethyl acetate (1.00 L), the organic phase was separated, washed with water (500 mL×3), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether/ethyl acetate = 1/0 to 2/1) to obtain 3-bromo-2-(trifluoromethyl)benzonitrile (29.0 g, 116 mmol, 72.3% yield).

¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 8.20 (d, J = 8.0 Hz, 1H), 8.10 (d, J = 7.6 Hz, 1H), 7.75 (t, J = 8.0 Hz, 1H).

Step B: Add 3-bromo-2-(trifluoromethyl)benzonitrile (29.0 g, 116 mmol, 1.00 equivalent) and tributyl(1-ethoxyvinyl) tin (50.3 g, 139 mmol, 47.0 mL, 1.20 equivalents) Pd(PPh ₃ ) ₄ (6.70 g, 5.80 mmol, 0.05 equivalents) was added to a solution in toluene (250 mL), and the mixture was stirred at 100° C. for 16 hours. The reaction mixture was cooled to 25°C, diluted with water (500 mL) and ethyl acetate (200 mL), and finally potassium fluoride (50.0 g) was added as a solid. The mixture was stirred at 25°C for 30 minutes, then the organic layer was separated, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 20/1 to 5/1) to obtain a crude product. The crude product was wet-milled with petroleum ether (50.0 mL), filtered, and the filtrate was concentrated under reduced pressure to obtain 3-(1-ethoxyvinyl)-2-(trifluoromethyl) as a pale yellow oil. ) Benzoonitrile (8.00 g, 33.2 mmol, 23.0% yield).

¹ H NMR (400 MHz, CDCl ₃ ) δ = 7.82 (d, J = 7.2 Hz, 1H), 7.70 (d, J = 7.2 Hz, 1H), 7.65-7.59 (t, J = 7.6 Hz, 1H), 4.37 (d, J = 2.8 Hz, 1H), 4.25 (d, J = 2.8 Hz, 1H), 3.90 (q, J = 7.2 Hz, 2H), 1.36 (t, J = 6.8 Hz, 3H).

Step C: Add hydrochloric acid ( 2.00 M, 29.0 mL, 2.00 equivalents), and the reaction mixture was stirred at 20°C for 2 hours. The pH of the mixture was then adjusted to pH=8 with aqueous sodium bicarbonate solution, and further diluted with water (100 mL). The resulting solution was extracted with ethyl acetate (50.0 mL×3), and the combined organic phase was washed with brine (100 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 20/1 to 5/1) to obtain 3-acetyl-2-(trifluoromethyl) as a colorless oil Benzoonitrile (5.30 g, 24.8 mmol, 85.6% yield).

¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 8.25 (dd, J = 0.8, 7.6 Hz, 1H), 8.07-7.94 (m, 2H), 2.60 (s, 3H).

Step d: Add 3-acetyl-2-(trifluoromethyl)benzonitrile (1.00 g, 4.69 mmol, 1.00 equivalent) and ( R ) -2 -methylpropane-2-sulfinamide (625 mg, 5.16 mmol, 1.10 equivalents) was added to a solution of tetrahydrofuran (2.00 mL) with 1,2-dimethoxyethane (423 mg, 4.69 mmol, 488 µL, 1.00 equivalent) and titanium (IV) ethoxide (3.21 g, 14.1 mmol, 2.92 mL, 3.00 equivalents), and the reaction mixture was stirred at 80°C for 16 hours. The mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate (100 mL) and poured into a mixture of diatomaceous earth (20.0 g) and saturated sodium bicarbonate (10.0 g) in water (100 mL) . The mixture was stirred, then filtered, and the filter cake was stirred and filtered with ethyl acetate (30.0 mL), and this process was repeated three times until the product filter cake was washed out. The combined filtrates were separated, and the aqueous phase was extracted with ethyl acetate (100 mL). The combined organic layer was washed with brine (50.0 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ethyl acetate/petroleum ether, 0-30%) to obtain ( R ) -N -(1-(3-cyano-2-() as a pale yellow oil Trifluoromethyl)phenyl)ethylene)-2-methylpropane-2-sulfinamide (950 mg, 2.99 mmol, 63.7% yield, 99.5% purity). LCMS [M+1] ⁺ : 317.1.

¹ H NMR (400 MHz, CDCl ₃ ) δ = 7.92-7.80 (m, 1H), 7.77-7.65 (m, 1H), 7.61-7.37 (m, 1H), 2.74-2.38 (m, 3H), 1.29- 1.24 (m, 9H).

Step E: To ( R ) -N -(1-(3-cyano-2-(trifluoromethyl)phenyl)ethyl)-2-methylpropane- To a solution of 2-sulfinamide (1.70 g, 5.37 mmol, 1.00 equivalent) in tetrahydrofuran (20.0 mL) was added sodium borohydride (610 mg, 16.0 mmol, 3.00 equivalent) in portions. After the addition, the mixture was stirred at this temperature for 30 minutes, and then warmed to 25°C and stirred for another 3 hours. Subsequently, under a nitrogen atmosphere at 25°C, the mixture was diluted dropwise with a saturated aqueous ammonium chloride solution (100 mL) while stirring, and then extracted with ethyl acetate (150 mL×2). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 5/1 to 1/1) to obtain ( R ) -N -(1-(3-cyanide) as a white solid 2-(trifluoromethyl)phenyl)ethyl)-2-methylpropane-2-sulfinamide (1.50 g, 4.71 mmol, 87.7% yield, mixture of diastereomers). LCMS [M+1] ⁺ : 319.1.

烷（10.0 mL）在5℃下攪拌30分鐘。在此時間後，形成白色沈澱物，且將懸浮液過濾。將濾餅收集且在真空下乾燥，得到呈白色固體狀之3-(1-胺基乙基)-2-(三氟甲基)苯甲腈（850 mg，3.39 mmol，77.1%產率，HCl鹽）。LCMS [M+1]⁺ : 215.1。Step F: Add ( R ) -N -(1-(3-cyano-2-(trifluoromethyl)phenyl)ethyl)-2-methylpropane-2-sulfinamide (1.4 g, 4.40 mmol, 1.00 equivalent) in HCl•two

Alkane (10.0 mL) was stirred at 5°C for 30 minutes. After this time, a white precipitate formed and the suspension was filtered. The filter cake was collected and dried under vacuum to give 3-(1-aminoethyl)-2-(trifluoromethyl)benzonitrile (850 mg, 3.39 mmol, 77.1% yield as a white solid). HCl salt). LCMS [M+1] ⁺ : 215.1.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 8.84 (s, 3H), 8.38 (br d, J =8.0 Hz, 1H), 8.19 (d, J =7.6 Hz, 1H), 8.12-7.95 ( m, 1H), 4.64 (br d, J =6.0 Hz, 1H), 1.56 (d, J =6.4 Hz, 3H).

（300 mg，1.40 mmol，1.00當量）、二異丙基乙胺（499 mg，3.86 mmol，673 µL，2.76當量）及氟化銫（400 mg，2.63 mmol，97.0 µL，1.88當量）於二甲基亞碸（1.50 mL）中之混合物脫氣且用氮氣沖洗（3次），且隨後將混合物在氮氣氛圍下在130℃下攪拌1小時。隨後將混合物冷卻至25℃且添加乙酸乙酯（60.0 mL），且將有機溶液用鹽水（30.0 mL×2）洗滌，經無水硫酸鈉乾燥，過濾且在減壓下濃縮。將殘餘物藉由管柱層析法（SiO₂ ，石油醚/乙酸乙酯＝5/1至1/1）純化，得到呈白色固體狀之3-(1-((7-氯-4-甲基吡啶并[3,4-d]嗒

-1-基)胺基)乙基)-2-(三氟甲基)苯甲腈（160 mg，408 µmol，29.2%產率）。LCMS [M+1]⁺ : 392.1。Step G: Combine 3-(1-aminoethyl)-2-(trifluoromethyl)benzonitrile (300 mg, 1.40 mmol, 1.00 equivalent, HCl salt), 1,7-dichloro-4-methyl Pyrido[3,4- d]

(300 mg, 1.40 mmol, 1.00 equivalent), diisopropylethylamine (499 mg, 3.86 mmol, 673 µL, 2.76 equivalent) and cesium fluoride (400 mg, 2.63 mmol, 97.0 µL, 1.88 equivalent) in dimethyl The mixture in pyromide (1.50 mL) was degassed and flushed with nitrogen (3 times), and then the mixture was stirred at 130°C for 1 hour under a nitrogen atmosphere. Then the mixture was cooled to 25°C and ethyl acetate (60.0 mL) was added, and the organic solution was washed with brine (30.0 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 5/1 to 1/1) to obtain 3-(1-((7-chloro-4- Pico[3,4-d]ta

-1-yl)amino)ethyl)-2-(trifluoromethyl)benzonitrile (160 mg, 408 µmol, 29.2% yield). LCMS [M+1] ⁺ : 392.1.

-1-基)胺基)乙基)-2-(三氟甲基)苯甲腈（160 mg）進一步使用SFC[管柱：DAICEL CHIRALPAK AD（250 mm×30 mm，10 um）；移動相：A相：（0.1% NH₄ OH）於MeOH中，B相：CO₂ ；B%：20%-20%]純化，得到第一溶離異構體，為呈白色固體狀之(R )-3-(1-((7-氯-4-甲基吡啶并[3,4-d ]嗒

-1-基)胺基)乙基)-2-(三氟甲基)苯甲腈（62.0 mg，158 µmol，39.0%產率）。LCMS [M+1]⁺ : 392.1。Add 3-(1-((7-chloro-4-methylpyrido[3,4-d]

-1-yl)amino)ethyl)-2-(trifluoromethyl)benzonitrile (160 mg) further use SFC [Column: DAICEL CHIRALPAK AD (250 mm×30 mm, 10 um); mobile phase ：Phase A: (0.1% NH ₄ OH) in MeOH, Phase B: CO ₂ ; B%: 20%-20%] Purify to obtain the first lysomer, which is a white solid ( R )- 3-(1-((7-chloro-4-methylpyrido[3,4- d ]

-1-yl)amino)ethyl)-2-(trifluoromethyl)benzonitrile (62.0 mg, 158 µmol, 39.0% yield). LCMS [M+1] ⁺ : 392.1.

¹ H NMR (400 MHz, CD ₃ OD) δ = 9.24 (d, J =0.8 Hz, 1H), 8.46 (d, J =0.8 Hz, 1H), 8.05 (d, J =8.4 Hz, 1H), 7.80 (d, J = 7.2 Hz, 1H), 7.71-7.57 (m, 1H), 5.74 (q, J = 6.8 Hz, 1H), 2.74 (s, 3H), 1.68 (d, J = 6.8 Hz, 3H) . Intermediate AF

Step A: Under nitrogen atmosphere, add palladium to a solution of 4-fluoro-3-nitro-5-(trifluoromethyl)benzoic acid (2.00 g, 7.90 mmol, 1.00 equivalent) in tetrahydrofuran (15.0 mL) /Carbon (7.90 mmol, 10% purity, 1.00 equivalent), and the mixture was stirred at 25°C for 2 hours under a hydrogen atmosphere (15 Psi). The mixture was then filtered and concentrated under reduced pressure to give the compound 3-amino-4-fluoro-5-(trifluoromethyl)benzoic acid (1.60 g, 7.17 mmol, 90.8% yield) as a white solid.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 7.68-7.64 (m, 1H), 7.32-7.29 (m, 1H), 5.95-5.89 (m, 2H).

Step B: Add 3-amino-4-fluoro-5-(trifluoromethyl)benzoic acid (1.50 g, 6.72 mmol, 1.00 equivalent) and N , O -dimethylhydroxylamine (830 mg, 13.45 mmol, 2.00 Equivalent) Add HATU (5.11 g, 13.5 mmol, 2.00 equiv) and N,N -diisopropylethylamine (2.61 g, 20.2 mmol ) to a solution in N,N-dimethylformamide (10.0 mL) , 3.50 mL, 3.00 equivalents), and the mixture was stirred at 25°C for 12 hours. The mixture was diluted with water (50.0 mL), and then extracted with ethyl acetate (50.0 mL×3). The combined organic layer was washed with brine (50.0 mL×3), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate = 10/1 to 3/1) to obtain the compound 3-amino-4-fluoro-N-methoxy as a yellow oil Benzyl-N-methyl-5-(trifluoromethyl)benzamide (1.50 g, 5.64 mmol, 83.9% yield).

¹ H NMR (400 MHz, CDCl ₃ ) δ = 7.38-7.34 (m, 2H), 3.57 (s, 3H), 3.36 (s, 3H)

Step C: Add 3-amino-4-fluoro-N-methoxy-N-methyl-5-(trifluoromethyl)benzamide (1.50 g, 5.64 mmol, 1.00 equivalent) in dichloromethane Add di-tertiary butyl dicarbonate (3.69 g, 16.9 mmol, 3.88 mL, 3.00 equivalents) and 4-dimethylaminopyridine (688 mg, 5.64 mmol, 1.00 equivalents) to the solution in (10.0 mL), and The mixture was stirred at 25°C for 12 hours. The reaction mixture was diluted with water (50.0 mL), and then extracted with ethyl acetate (50.0 mL×3). The combined organic layer was washed with brine (50.0 mL×3), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate = 10/1 to 3/1) to obtain a yellow oily compound (tertiary butoxycarbonyl) (2-fluoro- Tertiary butyl 5-(methoxy(methyl)aminomethanyl)-3-(trifluoromethyl)phenyl)carbamate (2.00 g, 4.29 mmol, 76.1% yield).

¹ H NMR (400 MHz, CDCl ₃ ) δ = 8.05-8.01 (m, 1H), 7.87-7.84 (m, 1H), 3.55 (s, 3H), 3.39 (s, 3H), 1.42 (s, 18H) .

Step D: At 0℃, to (tertiary butoxycarbonyl)(2-fluoro-5-(methoxy(methyl)aminomethanyl)-3-(trifluoromethyl)phenyl)amine To a solution of tert-butyl formate (1.80 g, 3.86 mmol, 1.00 equivalent) in tetrahydrofuran (20.0 mL) was added methylmagnesium bromide solution (3.00 M, 3.86 mL, 3.00 equivalent), and the mixture was kept at 0°C Stir for 12 hours. The reaction mixture was then diluted with water (100 mL), and the solution was extracted with ethyl acetate (100 mL×3). The combined organic layer was washed with brine (100 mL×3), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate = 10/1 to 3/1) to obtain a yellow oily compound (5-acetyl-2-fluoro-3- (Trifluoromethyl)phenyl) carbamate (1.10 g, 3.42 mmol, 88.7% yield).

¹ H NMR (400 MHz, CDCl ₃ ) δ = 8.98 (d, J = 6.4 Hz, 1H), 7.90-7.87 (m, 1H), 6.86 (s, 1H), 2.65 (s, 3H), 1.56 (s , 9H).

Step E: To (5-acetyl-2-fluoro-3-(trifluoromethyl)phenyl) carbamic acid tert-butyl ester (1.10 g, 2.61 mmol, 1.00 equivalent) and ( R )-2-methyl To a solution of methyl propane-2-sulfinamide (950 mg, 7.83 mmol, 3.00 equivalents) in tetrahydrofuran (10.0 mL) was added titanium(IV) isopropoxide (1.48 g, 5.22 mmol, 1.54 mL, 2.00 equivalents) And 1-methoxy-2-(2-methoxyethoxy)ethane (1.87 g, 13.97 mmol, 2.00 mL, 5.35 equivalents), and the mixture was stirred at 70° C. for 12 hours. The mixture was then diluted with water (50.0 mL), and extracted with ethyl acetate (50.0 mL×3). The combined organic layer was washed with brine (50.0 mL×3), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate = 10/1 to 3/1) to obtain the compound ( R )-(5-(1-((third butyl) as a yellow oil Tert-butyl sulfinyl)imino)ethyl)-2-fluoro-3-(trifluoromethyl)phenyl)carbamate (1.00 g, 2.36 mmol, 90.1% yield).

¹ H NMR (400 MHz, CDCl ₃ ) δ = 8.86 (d, J = 6.4 Hz, 1H), 7.82 (d, J = 6.0 Hz, 1H), 6.85 (s, 1H), 2.79 (s, 3H), 1.54 (s, 9H), 1.33 (s, 9H).

Step F: At 0℃, add ( R )-(5-(1-((tertiary butylsulfinyl)imino)ethyl)-2-fluoro-3-(trifluoromethyl) To a solution of tert-butyl phenyl)carbamate (1.00 g, 2.36 mmol, 1.00 equivalent) in tetrahydrofuran (10.0 mL) was added sodium borohydride (268 mg, 7.07 mmol, 3.00 equivalent), and the mixture was heated at 0°C Stir for 2 hours. The mixture was then diluted with water (50.0 mL), and extracted with ethyl acetate (50.0 mL×3). The combined organic layer was washed with brine (50.0 mL×3), dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate = 10/1 to 3/1) to obtain the compound (5-(( R )-1-((() R )-tert-butylsulfinyl)amino)ethyl)-2-fluoro-3-(trifluoromethyl)phenyl)carbamic acid tert-butyl ester (620 mg, 1.45 mmol, 61.7% yield Rate).

¹ H NMR (400 MHz, CDCl ₃ ) δ = 8.34 (d, J = 6.4 Hz, 1H), 7.23-7.20 (m, 1H), 6.80 (s, 1H), 4.56-5.53 (m, 1H), 1.54 -1.52 (m, 12H), 1.24 (s, 9H).

烷中，5.00 mL，13.76當量），且將混合物在25℃下攪拌1小時。隨後將混合物在減壓下濃縮，得到呈黃色油狀之化合物(R )-5-(1-胺基乙基)-2-氟-3-(三氟甲基)苯胺（280 mg，1.24 mmol，85.5%產率，98.6%純度，HCl鹽）。該化合物無需進一步純化即可直接使用。 中間物AG

Step G: To (5-(( R )-1-((( R )-tertiary butylsulfinyl)amino)ethyl)-2-fluoro-3-(trifluoromethyl)phenyl ) Tert-butyl carbamate (620 mg, 1.45 mmol, 1.00 equivalent) in dichloromethane (5.00 mL) was added hydrochloride (4.00 M in 1,4-di

In alkane, 5.00 mL, 13.76 equivalents), and the mixture was stirred at 25°C for 1 hour. The mixture was then concentrated under reduced pressure to give compound ( R )-5-(1-aminoethyl)-2-fluoro-3-(trifluoromethyl)aniline (280 mg, 1.24 mmol) as a yellow oil , 85.5% yield, 98.6% purity, HCl salt). The compound can be used directly without further purification. Intermediate AG

Step A: At -78°C, add DIBAL-H (1.0 M, 65.5 mL, 3.00 equivalents) for 10 minutes, and the reaction mixture was stirred at -78°C for 2 hours. The mixture was then diluted dropwise with water (2.50 mL) at 0°C under a nitrogen atmosphere, and then an aqueous sodium hydroxide solution (2.50 mL, w/w=15%) and water (6.26 mL) were added. The mixture was then stirred at 0°C for 30 minutes to obtain a suspension, the suspension was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=30/1 to 10/1) to obtain (4,6-dichloropyridin-2-yl) as a yellow oil Methanol (2.40 g, 13.5 mmol, 61.7% yield).

¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 7.65 (s, 1H), 7.52 (s, 1H), 5.69 (t, J = 6.0 Hz, 1H), 4.53 (d, J = 6.0 Hz, 2H ).

Step B: At 0°C, to a solution of (4,6-dichloropyridin-2-yl)methanol (2.40 g, 13.5 mmol, 1.00 equivalent) in dichloromethane (20.0 mL) was added in batches -Dess-Martin Periodane (11.4 g, 27.0 mmol, 8.35 mL, 2.00 equivalents), and the mixture was stirred at 20°C for 2 hours. The mixture was then poured into water (10.0 mL) and stirred for 15 minutes, then saturated aqueous sodium thiosulfate (20.0 mL) was slowly added, and the mixture was stirred for another 15 minutes. The suspension was filtered, the layers were separated, and the aqueous phase was extracted with DCM (20.0 mL×2). The combined organic layer was washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 50/1 to 10/1) to obtain 4,6-dichloropyridinecarboxaldehyde (1.60 g, 9.09 mmol, 67.4% yield).

¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 9.87 (s, 1H), 8.14 (d, J = 1.6 Hz, 1H), 8.01 (d, J = 1.6 Hz, 1H).

Step C: At -20°C, to a solution of 4,6-dichloropyridinecarboxaldehyde (1.10 g, 6.25 mmol, 1.00 equivalent) in dichloromethane (10.0 mL) was added dropwise diethylaminotrifluoro Sulfide (2.01 g, 12.5 mmol, 1.65 mL, 2.00 equivalents), and the mixture was stirred at 25°C for 1 hour. Then the mixture was slowly poured into saturated aqueous sodium bicarbonate (10.0 mL) at 25°C, and the resulting solution was extracted with ethyl acetate (10.0 mL×3). The combined organic phase was washed with brine (5.00 mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 100/1 to 20/1) to obtain 2,4-dichloro-6-(difluoromethyl) as a yellow oil Yl)pyridine (1.00 g, 5.05 mmol, 80.8% yield).

¹ H NMR (400 MHz, CD ₃ OD) δ = 7.75 (s, 1H), 7.74(s, 1H), 6.82-6.55 (m, 1H).

烷（10.0 mL）中之溶液中添加Pd(PPh₃ )₂ Cl₂ （390 mg，556 µmol，0.10當量），且將混合物在110℃下攪拌12小時。將反應混合物冷卻至25℃，且隨後緩慢倒入飽和氟化鉀水溶液（20.0 mL）中。將所得水溶液用乙酸乙酯（50.0 mL×3）萃取，且將合併之有機層用鹽水（30.0 mL×2）洗滌，經無水鈉乾燥，過濾，且在減壓下濃縮。將殘餘物藉由管柱層析法（SiO₂ ，石油醚/乙酸乙酯=100/1至20/1）純化，得到呈黃色油狀之4-氯-2-(二氟甲基)-6-(1-乙氧基乙烯基)吡啶（1.20 g，5.14 mmol，92.5%產率），其直接用於下一步。Step D: Under a nitrogen atmosphere, add tributyl(1-ethoxyvinyl)tin (2.01 g, 5.56 mmol, 1.88 mL, 1.00 equivalent) and 2,4-dichloro-6-(difluoromethyl) ) Pyridine (1.10 g, 5.56 mmol, 1.00 equivalent) in two

_{Pd(PPh 3} ) ₂ Cl ₂ (390 mg, 556 µmol, 0.10 equivalent) was added to the solution in alkane (10.0 mL), and the mixture was stirred at 110°C for 12 hours. The reaction mixture was cooled to 25°C, and then slowly poured into a saturated aqueous potassium fluoride solution (20.0 mL). The resulting aqueous solution was extracted with ethyl acetate (50.0 mL×3), and the combined organic layer was washed with brine (30.0 mL×2), dried over anhydrous sodium, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 100/1 to 20/1) to obtain 4-chloro-2-(difluoromethyl)- as a yellow oil 6-(1-ethoxyvinyl)pyridine (1.20 g, 5.14 mmol, 92.5% yield), which was used directly in the next step.

烷（5.00 mL）中之溶液中添加鹽酸水溶液（2.00 M，4.28 mL，2.00當量），且將混合物在20℃下攪拌1小時。隨後藉由添加飽和碳酸氫鈉（15.0 mL）將混合物pH調節至pH=8，且用乙酸乙酯（30.0 mL×2）萃取。將合併之有機相用鹽水（10.0 mL×2）洗滌，經無水硫酸鈉乾燥，過濾，且在減壓下濃縮。將殘餘物藉由管柱層析法（SiO₂ ，石油醚/乙酸乙酯= 50/1至10/1）純化，得到呈白色固體狀之1-(4-氯-6-(二氟甲基)吡啶-2-基)乙-1-酮（800 mg，3.89 mmol，90.9%產率）。At 20°C, add 4-chloro-2-(difluoromethyl)-6-(1-ethoxyvinyl)pyridine (1.00 g, 4.28 mmol, 1.00 equivalent) in two

To the solution in alkane (5.00 mL) was added aqueous hydrochloric acid (2.00 M, 4.28 mL, 2.00 equivalents), and the mixture was stirred at 20°C for 1 hour. Then the pH of the mixture was adjusted to pH=8 by adding saturated sodium bicarbonate (15.0 mL), and extracted with ethyl acetate (30.0 mL×2). The combined organic phase was washed with brine (10.0 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 50/1 to 10/1) to obtain 1-(4-chloro-6-(difluoromethyl) as a white solid (Yl)pyridin-2-yl)ethan-1-one (800 mg, 3.89 mmol, 90.9% yield).

¹ H NMR (400 MHz, CD ₃ OD) δ = 8.10-8.16 (m, 1H), 7.95 (d, J = 1.6 Hz, 1H), 6.67-6.95 (m, 1H), 2.69 (s, 3H).

烷（6.00 mL）中之溶液中添加碳酸銫（2.69 g，8.27 mmol，2.00當量）、XPhos（394 mg，827 µmol，0.20當量）及乙酸鈀（92.8 mg，413 µmol，0.10當量），且將混合物在90℃下攪拌2小時。隨後將混合物冷卻至25℃且在減壓下濃縮，且將殘餘物藉由管柱層析法（SiO₂ ，石油醚/乙酸乙酯=100/1至10/1）純化，得到呈白色固體狀之(2-乙醯基-6-(二氟甲基)吡啶-4-基)胺甲酸第三丁酯（1.00 g，3.49 mmol，84.5%產率）。LCMS [M+1]⁺ : 287.1。Step E: Under nitrogen atmosphere, add 1-(4-chloro-6-(difluoromethyl)pyridin-2-yl)ethan-1-one (0.85 g, 4.13 mmol, 1.00 equivalent) and carbamate to the third Butyl ester (1.45 g, 12.4 mmol, 3.00 equivalent) in two

Add cesium carbonate (2.69 g, 8.27 mmol, 2.00 equivalents), XPhos (394 mg, 827 µmol, 0.20 equivalents) and palladium acetate (92.8 mg, 413 µmol, 0.10 equivalents) to the solution in alkane (6.00 mL), and The mixture was stirred at 90°C for 2 hours. The mixture was then cooled to 25°C and concentrated under reduced pressure, and the residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 100/1 to 10/1) to obtain a white solid (2-Acetyl-6-(difluoromethyl)pyridin-4-yl) tert-butyl carbamate (1.00 g, 3.49 mmol, 84.5% yield) in the form. LCMS [M+1] ⁺ : 287.1.

Step F: To (2-acetyl-6-(difluoromethyl)pyridin-4-yl) carbamic acid tert-butyl ester (1.00 g, 3.49 mmol, 1.00 equivalent) and ( S )-2-methyl To a solution of propane-2-sulfinamide (508 mg, 4.19 mmol, 1.20 equivalents) in THF (10.0 mL) was added titanium(IV) ethoxide (7.97 g, 34.9 mmol, 7.24 mL, 10.0 equivalents), and The mixture was stirred at 75°C for 12 hours. The mixture was then cooled to 25°C and poured into water (5.00 mL), then the suspension was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 50/1 to 5/1) to obtain ( S )-(2-(1-((第Tributylsulfinyl)imino)ethyl)-6-(difluoromethyl)pyridin-4-yl)carbamate (1.00 g, 2.57 mmol, 73.5% yield).

¹ H NMR (400 MHz, CD ₃ OD) δ = 8.30 (s, 1H), 7.94 (d, J = 1.6 Hz, 1H), 6.52-6.82 (m, 1H), 2.81 (s, 3H), 1.54 ( s, 9H), 1.35 (s, 9H).

Step G: At 0 ℃, to ( S )-(2-(1-((tertiary butylsulfinyl)imino)ethyl)-6-(difluoromethyl)pyridine-4- To a solution of tert-butyl carbamate (1.00 g, 2.57 mmol, 1.00 equivalent) in THF (10.0 mL) was added dropwise lithium tri-second butyl borohydride (1.0 M, 976 mg, 5.14 mmol, 1.12). mL, 2.00 equivalents), and the mixture was stirred at 0-20°C for 1 hour. The mixture was poured into a saturated aqueous ammonium chloride solution (15.0 mL) and stirred for 10 minutes, followed by extraction with ethyl acetate (15.0 mL×3). The combined organic phase was washed with brine (15.0 mL×3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 100/1 to 5/1) to obtain (2-(( R )-1-((() S )-tert-butylsulfinyl)amino)ethyl)-6-(difluoromethyl)pyridin-4-yl)carbamic acid tert-butyl ester (550 mg, 1.26 mmol, 49.0% yield , 89.5% purity).

¹ H NMR (400 MHz, CD ₃ OD) δ = 7.70 (s, 1H), 7.61 (d, J = 2.0 Hz, 1H), 6.41-6.77 (m, 1H), 4.55 (q, J = 6.8 Hz, 1H), 1.58 (d, J = 6.8 Hz, 3H), 1.53 (s, 9H), 1.23 (s, 9H).

SFC: Column: Chiralcel OD-3 50×4.6 mm inner diameter, 3 um; mobile phase: phase A is CO ₂ and phase B is MeOH (0.05% DEA); gradient dissolution: MeOH (0.05% DEA) in 5 % To 40% CO ₂ ; flow rate: 3 ml/min; detector: PDA; column temperature: 35°C; back pressure: 100 Bar.

烷（2.00 mL）中之溶液在0-20℃下攪拌1小時。隨後將混合物在減壓下濃縮以得到呈白色固體狀之(R )-2-(1-胺基乙基)-6-(二氟甲基)吡啶-4-胺及(2-((R )-1-(((S )-第三丁基亞磺醯基)胺基)乙基)-6-(二氟甲基)吡啶-4-基)胺甲酸第三丁酯之混合物，其無需純化即可直接用於下一步。LCMS [M+1]⁺ : 288.2。Step H: Add (2-(( R )-1-((( S )-tertiary butylsulfinyl)amino)ethyl)-6-(difluoromethyl)pyridin-4-yl) Tertiary butyl carbamate (450 mg, 1.15 mmol, 1.00 equivalent) in hydrochloric acid/two

The solution in alkane (2.00 mL) was stirred at 0-20°C for 1 hour. The mixture was then concentrated under reduced pressure to obtain ( R )-2-(1-aminoethyl)-6-(difluoromethyl)pyridin-4-amine and (2-(( R )-1-((( S )-tertiary butylsulfinyl)amino)ethyl)-6-(difluoromethyl)pyridin-4-yl) a mixture of tertiary butyl carbamate, which It can be used directly in the next step without purification. LCMS [M+1] ⁺ : 288.2.

¹ H NMR (400 MHz, CD ₃ OD) δ = 7.74 (s, 1H), 7.65 (d, J = 1.6 Hz, 1H), 6.82-6.51 (m, 1H), 4.60-4.45 (m, 2 H) , 1.61 (d, J = 6.8 Hz, 3H), 1.54 (s, 9H). Intermediate AH

Step A: Under a nitrogen atmosphere, add 1-(2-fluoro-3-methylphenyl)ethan-1-one (1.00 g, 6.57 mmol, 1.00 equivalent) and ( S )-2-methylpropane-2 -To a solution of sulfinamide (1.04 g, 8.54 mmol, 1.30 equivalents) in tetrahydrofuran (20.0 mL) was added titanium tetraisopropoxide (3.73 g, 13.1 mmol, 3.88 mL, 2.00 equivalents), and the mixture was placed under nitrogen Stir at 70°C for 12 hours under the atmosphere. The reaction mixture was cooled to 25°C and poured into water (40.0 mL) after stirring for 10 minutes to obtain a suspension, the suspension was filtered, and the resulting aqueous solution was extracted with ethyl acetate (40.0 mL×3). The combined organic layer was washed with brine (30.0 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate = 50/1 to 2/1) to obtain ( S ) -N -(1-(2-fluoro-) as a yellow solid 3-Methylphenyl)ethyl)-2-methylpropane-2-sulfinamide (1.50 g, 5.87 mmol, 89.4% yield). LCMS [M+1] ⁺ : 256.2.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 7.46 (br t, J = 6.8 Hz, 1H), 7.30-7.24 (m, 1H), 7.09-7.04 (m, 1H), 2.76 (br d, J = 2.8 Hz, 3H), 2.31 (d, J = 2.4 Hz, 3H), 1.31 (s, 9H).

Step B: To (S ) -N -(1-(2-fluoro-3-methylphenyl)ethylene)-2-methylpropane-2-sulfinic acid at -78°C under a nitrogen atmosphere To a solution of amide (1.50 g, 5.87 mmol, 1.00 equivalent) in tetrahydrofuran (20.0 mL) was added lithium tri-second butyl borohydride (1.0 M, 11.7 mmol, 11.8 mL, 2.00 equivalent), and the mixture was heated at- Stir at 78°C for 2 hours. The reaction mixture was slowly poured into water (10.0 mL) and stirred for 10 minutes, and the resulting mixed solution was extracted with ethyl acetate (10.0 mL×3). The combined organic layer was washed with brine (10.0 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate = 50/1 to 1/1) to obtain ( S )-N-(1-(2-fluoro- 3-Methylphenyl)ethyl)-2-methylpropane-2-sulfinamide (900 mg, 3.50 mmol, 59.5% yield). LCMS [M+1] ⁺ : 258.4.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 7.16 (t, J = 7.6 Hz, 1H), 7.13-7.08 (m, 1H), 7.04-6.99 (m, 1H), 4.85 (q, J = 6.8 Hz, 1H), 2.28 (d, J = 2.0 Hz, 3H), 1.58 (d, J = 6.8 Hz, 3H), 1.20 (s, 9H).

烷中，5.00 mL，5.72當量），且將混合物在20℃下攪拌1小時。將混合物濃縮，得到呈黃色固體狀之1-(2-氟-3-甲基苯基)乙-1-胺（390 mg，粗製，鹽酸鹽），其無需進一步純化即可直接使用。Step C: Under nitrogen atmosphere, to ( S )-N-(1-(2-fluoro-3-methylphenyl)ethyl)-2-methylpropane-2-sulfinamide (900 mg, 3.50 mmol, 1.00 equivalent) in dichloromethane (5.00 mL) was added HCl (4.00 M in 1,4-bis

In alkane, 5.00 mL, 5.72 equivalents), and the mixture was stirred at 20°C for 1 hour. The mixture was concentrated to give 1-(2-fluoro-3-methylphenyl)ethan-1-amine (390 mg, crude, hydrochloride) as a yellow solid, which was used directly without further purification.

（419 mg，1.96 mmol，1.00當量）、N,N- 二異丙基乙胺（506 mg，3.92 mmol，2.00當量）及氟化鉀（341 mg，5.87 mmol，0.14 mL，3.00當量）於二甲基亞碸（5.00 mL）中之溶液在氮氣氛圍下在130℃下攪拌1小時。隨後將混合物冷卻至25℃，倒入水（20.0 mL）中，且用乙酸乙酯（20.0 mL×3）萃取。將合併之有機層用鹽水（20.0 mL）洗滌，經硫酸鈉乾燥，過濾，且在減壓下濃縮。將殘餘物藉由製備型HPLC[管柱：Welch Xtimate C18 150×25 mm×5 um；移動相：A相：水（0.05% HCl），B相：乙腈；B%：14%-44%]純化，得到呈黃色固體狀之7-氯-N -(1-(2-氟-3-甲基苯基)乙基)-4-甲基吡啶并[3,4-d ]嗒

-1-胺（100 mg，0.30 mmol，23.2%產率）。LCMS [M+1]⁺ : 331.2。The 1-(2-fluoro-3-methylphenyl) ethyl-1-amine (300 mg, 1.96 mmol, 1.00 equivalent, hydrochloride), 1,7-dichloro-4-methylpyrido[3 ,4- d ]

(419 mg, 1.96 mmol, 1.00 equivalent), N,N -diisopropylethylamine (506 mg, 3.92 mmol, 2.00 equivalent) and potassium fluoride (341 mg, 5.87 mmol, 0.14 mL, 3.00 equivalent) in two The solution of methyl sulfoxide (5.00 mL) was stirred at 130°C for 1 hour under a nitrogen atmosphere. The mixture was then cooled to 25°C, poured into water (20.0 mL), and extracted with ethyl acetate (20.0 mL×3). The combined organic layer was washed with brine (20.0 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to preparative HPLC [column: Welch Xtimate C18 150×25 mm×5 um; mobile phase: phase A: water (0.05% HCl), phase B: acetonitrile; B%: 14%-44%] Purified to obtain 7-chloro- N -(1-(2-fluoro-3-methylphenyl)ethyl)-4-methylpyrido[3,4- d ] as a yellow solid

-1-amine (100 mg, 0.30 mmol, 23.2% yield). LCMS [M+1] ⁺ : 331.2.

-1-胺（200 mg，0.60 mmol，1.00當量）藉由SFC（管柱：DAICEL CHIRALPAK IG（250 mm×30 mm，10 um）；移動相：A相：0.1% NH₄ OH於MeOH中，B相：CO₂ ；B%：30%-30%]純化，得到第一溶離異構體，為呈黃色固體狀之(R )-7-氯-N-(1-(2-氟-3-甲基苯基)乙基)-4-甲基吡啶并[3,4-d]嗒

-1-胺（80.0 mg，0.24 mmol，40.0%產率）。The racemic 7-chloro- N -(1-(2-fluoro-3-methylphenyl)ethyl)-4-methylpyrido[3,4- d ]

-1-amine (200 mg, 0.60 mmol, 1.00 equivalent) by SFC (column: DAICEL CHIRALPAK IG (250 mm×30 mm, 10 um); mobile phase: Phase A: 0.1% NH ₄ OH in MeOH, Phase B: CO ₂ ; B%: 30%-30%] purified to obtain the first lysomer, which is ( R )-7-chloro-N-(1-(2-fluoro-3) in the form of a yellow solid -Methylphenyl)ethyl)-4-methylpyrido[3,4-d]ta

-1-amine (80.0 mg, 0.24 mmol, 40.0% yield).

-1-胺

The following examples are intended to illustrate certain other embodiments of the present invention and are not intended to limit the scope of the present invention. Example 1-1 6,7-Dimethoxy- N -(1-(4-(2-((methylamino)methyl)phenyl)thiophen-2-yl)ethyl)

-1-amine

（120 mg，534 µmol，1.00當量）、(2-(5-(1-胺基乙基)噻吩-3-基)苯甲基)(甲基)胺甲酸第三丁酯（130 mg，374 µmol，0.70當量）、BrettPhos Pd G₃ （48.4 mg，53.4 µmol，0.10當量）及第三丁醇鉀（150 mg，1.34 mmol，2.50當量）於甲苯（3.00 mL）中之混合物脫氣且用氮氣沖洗3次，隨後將反應混合物在氮氣氛圍下在100℃下攪拌1小時。將反應混合物冷卻至25℃且過濾，且將濾液在減壓下濃縮，得到殘餘物。將殘餘物藉由製備型TLC（SiO₂ ，二氯甲烷/甲醇=10/1）純化，得到呈褐色固體狀之(2-(5-(1-((6,7-二甲氧基呔

-1-基)胺基)乙基)噻吩-3-基)苯甲基)(甲基)胺甲酸第三丁酯（70.0 mg，24.5%產率）。LCMS [M+1]: 535.5。Step A: Add 1-chloro-6,7-dimethoxy

(120 mg, 534 µmol, 1.00 equivalent), (2-(5-(1-aminoethyl)thiophen-3-yl)benzyl)(methyl) carbamate (130 mg, 374 µmol, 0.70 equivalent), BrettPhos Pd G ₃ (48.4 mg, 53.4 µmol, 0.10 equivalent) and a mixture of potassium tert-butoxide (150 mg, 1.34 mmol, 2.50 equivalent) in toluene (3.00 mL), degassed with nitrogen After rinsing 3 times, the reaction mixture was stirred at 100°C for 1 hour under a nitrogen atmosphere. The reaction mixture was cooled to 25°C and filtered, and the filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by preparative TLC (SiO ₂ , dichloromethane/methanol=10/1) to obtain (2-(5-(1-((6,7-dimethoxyl

-1-yl)amino)ethyl)thiophen-3-yl)benzyl)(methyl)carbamate (70.0 mg, 24.5% yield). LCMS [M+1]: 535.5.

-1-基)胺基)乙基)噻吩-3-基)苯甲基)(甲基)胺甲酸第三丁酯（60.0 mg，112 µmol，1.00當量）於乙腈（1.00 mL）中之溶液中添加HCl（4.0 M於二

烷中，0.20 mL）。將反應混合物在25℃下攪拌10分鐘，隨後在25℃下將混合物過濾且在減壓下濃縮，得到殘餘物。將殘餘物溶於甲醇（2.00 mL）中，且用固體碳酸氫鈉（約30.0 mg）調節至pH＝7，得到懸浮液。將懸浮液過濾，且將濾液藉由製備型HPLC（管柱：Waters Xbridge 150×25 mm×5 um；移動相：[水（10 mM NH₄ HCO₃ ）-ACN]；B%：19%-49%，9分鐘）純化且凍乾，得到呈白色固體狀之6,7-二甲氧基-N -(1-(4-(2-((甲基胺基)甲基)苯基)噻吩-2-基)乙基)呔

-1-胺（16.6 mg，33.8%產率，99.6%純度）。LCMS [M+1]: 435.1。Step B: To (2-(5-(1-((6,7-Dimethoxy

-1-yl)amino)ethyl)thiophen-3-yl)benzyl)(methyl) tert-butyl carbamate (60.0 mg, 112 µmol, 1.00 equivalent) in acetonitrile (1.00 mL) Add HCl (4.0 M to two

In alkane, 0.20 mL). The reaction mixture was stirred at 25°C for 10 minutes, and then the mixture was filtered at 25°C and concentrated under reduced pressure to obtain a residue. The residue was dissolved in methanol (2.00 mL) and adjusted to pH=7 with solid sodium bicarbonate (about 30.0 mg) to obtain a suspension. The suspension was filtered, and the filtrate was subjected to preparative HPLC (column: Waters Xbridge 150×25 mm×5 um; mobile phase: [Water (10 mM NH ₄ HCO ₃ )-ACN]; B%: 19%- 49%, 9 minutes) purified and lyophilized to obtain 6,7-dimethoxy- N -(1-(4-(2-((methylamino)methyl)phenyl) as a white solid Thiophen-2-yl) ethyl) 呔

-1-amine (16.6 mg, 33.8% yield, 99.6% purity). LCMS [M+1]: 435.1.

-1-胺

¹ H NMR (400 MHz, CD ₃ OD) δ 8.73 (d, J = 2.4 Hz, 1H), 7.75 (s, 1H), 7.51-7.46 (m, 1H), 7.43-7.37 (m, 3H), 7.35 (d, J = 5.2 Hz, 1H), 7.19 (d, J = 1.2 Hz, 1H), 7.16 (s, 1H), 5.93-5.81 (m, 1H), 4.10 (s, 2H), 4.05 (s, 3H), 4.00 (s, 3H), 2.45 (s, 3H), 1.83 (d, J = 6.8 Hz, 3H). Example 1-2 ( R )-7-(1-methyl-1 H -pyrazol-4-yl) -N -(1-(4-(2-((methylamino)methyl)phenyl )Thien-2-yl)ethyl) 呔

-1-amine

-1-醇（950 mg，4.22 mmol，1.00當量）於乙腈（19.0 mL）中之溶液中添加三氯氧磷（V）（2.27 g，14.8 mmol，1.37 mL，3.50當量），將反應混合物在80℃下攪拌2小時。將反應混合物冷卻至25℃且真空濃縮以移除溶劑。用冷卻至0℃之DCM（50.0 mL）稀釋剩餘殘餘物，且用飽和碳酸氫鈉水溶液（30.0 mL）將有機層調節至pH=7。分離有機相，用鹽水（30.0 mL×2）洗滌，經無水硫酸鈉乾燥，過濾，且在減壓下濃縮，得到呈褐色固體狀之7-溴-1-氯呔

（900 mg，3.70 mmol，87.6%產率）。LCMS [M+3]: 244.8。Step A: To 7-bromo

-1-ol (950 mg, 4.22 mmol, 1.00 equivalent) in acetonitrile (19.0 mL) was added phosphorus oxychloride (V) (2.27 g, 14.8 mmol, 1.37 mL, 3.50 equivalent), and the reaction mixture Stir at 80°C for 2 hours. The reaction mixture was cooled to 25°C and concentrated in vacuo to remove the solvent. The remaining residue was diluted with DCM (50.0 mL) cooled to 0°C, and the organic layer was adjusted to pH=7 with saturated aqueous sodium bicarbonate solution (30.0 mL). The organic phase was separated, washed with brine (30.0 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 7-bromo-1-chlorobenzene as a brown solid

(900 mg, 3.70 mmol, 87.6% yield). LCMS [M+3]: 244.8.

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.44 (d, J = 0.8 Hz, 1H), 8.52-8.49 (m, 1H), 8.10 (dd, J = 2.0, 8.8 Hz, 1H), 7.90 (d, J = 8.4 Hz, 1H).

（100 mg，411 µmol，1.00當量）於DMSO（2.00 mL）中之溶液中添加(R )-(2-(5-(1-胺基乙基)噻吩-3-基)苯甲基)(甲基)胺甲酸第三丁酯（129 mg，370 µmol，0.90當量）、氟化鉀（71.6 mg，1.23 mmol，28.8 µL，3.00當量）及二異丙基乙胺（106 mg，821 µmol，143 µL，2.00當量）。將反應混合物在氮氣氛圍下在130℃下攪拌4小時。在此時間後，將反應混合物冷卻至25℃。向反應混合物中添加乙酸乙酯（10.0 mL）及水（8.00 mL），且分離各層，隨後用乙酸乙酯（10.0 mL×2）萃取水相。將合併之有機層用鹽水（10.0 mL×2）洗滌，經硫酸鈉乾燥，過濾，且在減壓下濃縮，得到殘餘物。將殘餘物藉由製備型TLC（SiO₂ ，石油醚/乙酸乙酯＝1/1）純化，得到呈黃色固體狀之(R )-(2-(5-(1-((7-溴呔

-1-基)胺基)乙基)噻吩-3-基)苯甲基)(甲基)胺甲酸第三丁酯（80.0 mg，35.2產率）。LCMS [M+1]: 553.0。Step B: To 7-bromo-1-chloro

(100 mg, 411 µmol, 1.00 equivalent) in DMSO (2.00 mL) was added ( R )-(2-(5-(1-aminoethyl)thiophen-3-yl)benzyl)( (Methyl) tert-butyl carbamate (129 mg, 370 µmol, 0.90 equivalent), potassium fluoride (71.6 mg, 1.23 mmol, 28.8 µL, 3.00 equivalent) and diisopropylethylamine (106 mg, 821 µmol, 143 µL, 2.00 equivalent). The reaction mixture was stirred at 130°C for 4 hours under a nitrogen atmosphere. After this time, the reaction mixture was cooled to 25°C. To the reaction mixture were added ethyl acetate (10.0 mL) and water (8.00 mL), and the layers were separated, and then the aqueous phase was extracted with ethyl acetate (10.0 mL×2). The combined organic layer was washed with brine (10.0 mL×2), dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by preparative TLC (SiO ₂ , petroleum ether/ethyl acetate = 1/1) to obtain ( R )-(2-(5-(1-((7-bromine) as a yellow solid

-1-yl)amino)ethyl)thiophen-3-yl)benzyl)(methyl)carbamate (80.0 mg, 35.2 yield). LCMS [M+1]: 553.0.

¹ H NMR (400 MHz, CD ₃ OD) δ 8.80 (s, 1H), 8.56 (s, 1H), 8.20 (s, 1H), 8.12-8.07 (m, 2H), 7.91 (br d, J = 8.4 Hz, 1H), 7.33-7.25 (m, 3H), 7.19 (br d, J = 7.2 Hz, 1H), 7.15-7.03 (m, 2H), 5.90-5.97 (m, 1H), 4.45 (br d, J = 14.8 Hz, 2H), 3.97 (s, 3H), 2.66 (s, 3H), 1.84 (d, J = 6.8 Hz, 3H), 1.46-1.29 (m, 9H).

-1-基)胺基)乙基)噻吩-3-基)苯甲基)胺甲酸第三丁酯（18.0 mg，32.5 µmol，1.00當量）於DCM（1.00 mL）中之溶液中添加TFA（770 mg，6.75 mmol，0.50 mL，208當量）。將反應混合物在25℃下攪拌10分鐘。過濾反應混合物，且在減壓下濃縮，得到殘餘物。將殘餘物藉由製備型HPLC（管柱：Phenomenex Luna C18 75×30 mm×3 um；移動相：[水（0.05% HCl）-ACN]；B%：13%-33%）純化且凍乾，得到呈灰白色固體狀之(R )-7-(1-甲基-1H -吡唑-4-基)-N -(1-(4-(2-((甲基胺基)甲基)苯基)噻吩-2-基)乙基)呔

-1-胺（9.02 mg，55.7%產率，91.1%純度）。LCMS [M+1]: 455.2。Step D: To ( R )-methyl(2-(5-(1-((7-(1-methyl-1 H -pyrazol-4-yl)

-1-yl) amino) ethyl) thiophen-3-yl) benzyl) tertiary butyl carbamate (18.0 mg, 32.5 µmol, 1.00 equivalent) in DCM (1.00 mL) was added TFA ( 770 mg, 6.75 mmol, 0.50 mL, 208 equivalents). The reaction mixture was stirred at 25°C for 10 minutes. The reaction mixture was filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 75×30 mm×3 um; mobile phase: [water (0.05% HCl)-ACN]; B%: 13%-33%) and lyophilized , To obtain (R )-7-(1-methyl-1 H -pyrazol-4-yl) -N -(1-(4-(2-((methylamino)methyl) as an off-white solid )Phenyl)thiophen-2-yl)ethyl)

-1-amine (9.02 mg, 55.7% yield, 91.1% purity). LCMS [M+1]: 455.2.

啉基呔

-1-胺

¹ H NMR (400 MHz, CD ₃ OD) δ 9.10 (br s, 1H), 8.49 (s, 1H), 8.39 (dd, J = 1.2, 8.4 Hz, 1H), 8.29 (s, 1H), 8.23 ( br d, J = 8.4 Hz, 1H), 8.17 (s, 1H), 8.08 (s, 1H), 7.60-7.57 (m, 1H), 7.50-7.45 (m, 2H), 7.44-7.40 (m, 1H) ), 7.39-7.34 (m, 2H), 5.78 (q, J = 6.4 Hz, 1H), 4.30 (s, 2H), 4.04 (s, 2H), 4.01 (s, 3H), 2.62 (s, 3H) , 1.98 (br d, J = 6.8 Hz, 3H). Example 1-3 ( R ) -N -(1-(4-(2-((methylamino)methyl)phenyl)thiophen-2-yl)ethyl)-7-

Linyl

-1-amine

-1-基)胺基)乙基)噻吩-3-基)苯甲基)(甲基)胺甲酸第三丁酯（45.0 mg，81.3 µmol，1.00當量）、

啉（10.6 mg，122 µmol，10.7 µL，1.50當量）、Pd₂ (dba)₃ （7.44 mg，8.13 µmol，0.10當量）、RuPhos（7.59 mg，16.3 µmol，0.20當量）及第三丁醇鉀（1.00 M於THF中，163 µL，2.00當量）於甲苯（3.00 mL）中之混合物脫氣且用氮氣沖洗3次，隨後將反應混合物在氮氣氛圍下在110℃下攪拌1小時。將反應混合物冷卻至25℃，且在減壓下濃縮，得到殘餘物。將殘餘物藉由管柱層析法（SiO₂ ，二氯甲烷/甲醇＝100/1至20/1）純化，得到呈黃色固體狀之(R )-甲基(2-(5-(1-((7-

啉基呔

-1-基)胺基)乙基)噻吩-3-基)苯甲基)胺甲酸第三丁酯（40.0 mg，57.2 µmol，70.3%產率，80.0%純度）。LCMS [M+1]: 560.2。Step A: Add ( R )-(2-(5-(1-((7-Bromo

-1-yl)amino)ethyl)thiophen-3-yl)benzyl)(methyl) tertiary butyl carbamate (45.0 mg, 81.3 µmol, 1.00 equivalent),

_{Pd 2} (dba) ₃ (7.44 mg, 8.13 µmol, 0.10 equivalent), RuPhos (7.59 mg, 16.3 µmol, 0.20 equivalent) and potassium tertiary butoxide (10.6 mg, 122 µmol, 10.7 µL, 1.50 equivalent), Pd 2 (dba) 3 (7.44 mg, 8.13 µmol, 0.20 equivalent) A mixture of 1.00 M in THF, 163 µL, 2.00 equivalents) in toluene (3.00 mL) was degassed and flushed with nitrogen 3 times, then the reaction mixture was stirred at 110°C for 1 hour under a nitrogen atmosphere. The reaction mixture was cooled to 25°C and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO ₂ , dichloromethane/methanol = 100/1 to 20/1) to obtain ( R )-methyl (2-(5-(1) as a yellow solid -((7-

Linyl

-1-yl)amino)ethyl)thiophen-3-yl)benzyl)tert-butyl carbamate (40.0 mg, 57.2 µmol, 70.3% yield, 80.0% purity). LCMS [M+1]: 560.2.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.81 (s, 1H), 7.72 (d, J = 8.8 Hz, 1H), 7.46-7.41 (m, 1H), 7.35-7.28 (m, 3H), 7.26- 7.06 (m, 3H), 7.03 (d, J =1.2 Hz, 1H), 6.15-5.95 (m, 1H), 4.80-4.40 (m, 2H), 3.96-3.86 (m, 4H), 3.46-3.28 ( m, 4H), 2.80-2.52 (m, 3H), 1.83 (d, J = 6.8 Hz, 3H), 1.42 (s, 9H).

啉基呔

-1-基)胺基)乙基)噻吩-3-基)苯甲基)胺甲酸第三丁酯（37.0 mg，52.9 µmol，1.00當量）於乙腈（1.00 mL）中之溶液中逐滴添加HCl（4.00 M於二

烷中，0.50 mL），將反應混合物在0℃下攪拌30分鐘。向混合物中添加甲醇（2.00 mL），且用固體碳酸氫鈉（約30.0 mg）調節至pH＝7，得到懸浮液，將該懸浮液過濾，將濾液真空濃縮，得到殘餘物。將殘餘物藉由製備型HPLC（管柱：Waters Xbridge 150 ×25 mm×5 um；移動相：[A：水（10 mM NH₄ HCO₃ ）-B：ACN]；B%：22%-52%]純化，得到呈白色固體狀之(R )-N -(1-(4-(2-((甲基胺基)甲基)苯基)噻吩-2-基)乙基)-7-

啉基呔

-1-胺（18.3 mg，38.5 µmol，72.7%產率，96.6%純度）。LCMS [M+1]: 460.2。Step B: At 0 ℃, to ( R )-methyl (2-(5-(1-((7-

Linyl

-1-yl)amino)ethyl)thiophen-3-yl)benzyl)t-butyl carbamate (37.0 mg, 52.9 µmol, 1.00 equivalent) in acetonitrile (1.00 mL) was added dropwise HCl (4.00 M in two

In alkane, 0.50 mL), the reaction mixture was stirred at 0°C for 30 minutes. To the mixture was added methanol (2.00 mL) and adjusted to pH=7 with solid sodium bicarbonate (about 30.0 mg) to obtain a suspension, which was filtered, and the filtrate was concentrated in vacuo to obtain a residue. The residue was subjected to preparative HPLC (column: Waters Xbridge 150 × 25 mm × 5 um; mobile phase: [A: water (10 mM NH ₄ HCO ₃ )-B: ACN]; B%: 22%-52 %] Purification to obtain ( R ) -N -(1-(4-(2-((methylamino)methyl)phenyl)thiophen-2-yl)ethyl)-7- as a white solid

Linyl

-1-amine (18.3 mg, 38.5 µmol, 72.7% yield, 96.6% purity). LCMS [M+1]: 460.2.

啉基呔

-1-胺

¹ H NMR (400 MHz, CD ₃ OD) δ 8.66 (s, 1H), 7.82 (dd, J = 1.2, 8.8 Hz, 1H), 7.65-7.60 (m, 1H), 7.55 (d, J = 2.0 Hz , 1H), 7.46-7.41 (m, 1H), 7.36-7.30 (m, 3H), 7.18 (d, J = 5.2 Hz, 2H), 5.94 (q, J = 6.8 Hz, 1H), 3.93-3.87 ( m, 4H), 3.81 (s, 2H), 3.49-3.43 (m, 4H), 2.28 (s, 3H), 1.84 (d, J = 6.8 Hz, 3H). Example 1-4 ( R ) -N -(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-7-

Linyl

-1-amine

（244 mg，1.00 mmol，1.00當量）及(R )-1-(2-甲基-3-(三氟甲基)苯基)乙-1-胺（242 mg，1.00 mmol，1.00當量，鹽酸鹽）於DMSO（3.00 mL）中之溶液中添加氟化鉀（175 mg，3.00 mmol，70.4 µL，3.00當量）及DIEA（259 mg，2.00 mmol，349 µL，2.00當量），將反應混合物在氮氣氛圍下在130℃下攪拌12小時。將反應混合物冷卻至25℃，且用乙酸乙酯（20.0 mL）稀釋，將有機層用鹽水（20.0 mL×2）洗滌，經無水硫酸鈉乾燥，過濾且真空濃縮，得到殘餘物。將殘餘物藉由矽膠層析法（石油醚/乙酸乙酯＝10/1至1/1）純化，得到呈褐色固體狀之(R )-7-溴-N -(1-(2-甲基-3-(三氟甲基)苯基)乙基)呔

-1-胺（280 mg，683 µmol，68.2%產率）。LCMS [M+1]: 409.9。Step A: To 7-bromo-1-chloro

(244 mg, 1.00 mmol, 1.00 equivalent) and ( R )-1-(2-methyl-3-(trifluoromethyl)phenyl)ethan-1-amine (242 mg, 1.00 mmol, 1.00 equivalent, salt Add potassium fluoride (175 mg, 3.00 mmol, 70.4 µL, 3.00 equivalent) and DIEA (259 mg, 2.00 mmol, 349 µL, 2.00 equivalent) to a solution of DMSO (3.00 mL) in DMSO (3.00 mL). Stir at 130°C for 12 hours under a nitrogen atmosphere. The reaction mixture was cooled to 25°C and diluted with ethyl acetate (20.0 mL), the organic layer was washed with brine (20.0 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to obtain a residue. The residue was purified by silica gel chromatography (petroleum ether/ethyl acetate = 10/1 to 1/1) to obtain ( R )-7-bromo- N -(1-(2-methyl) as a brown solid 3-(trifluoromethyl)phenyl)ethyl)

-1-amine (280 mg, 683 µmol, 68.2% yield). LCMS [M+1]: 409.9.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.92 (s, 1H), 7.94 (s, 1H), 7.91 (dd, J = 1.6, 8.4 Hz, 1H), 7.71 (d, J = 8.4 Hz, 1H) , 7.68 (d, J = 7.6 Hz, 1H), 7.58 (d, J = 8.0 Hz, 1H), 7.32-7.28 (m, 1H), 6.02-5.94 (m, 1H), 5.14 (br d, J = 6.4 Hz, 1H), 2.58 (s, 3H), 1.70 (d, J = 6.8 Hz, 3H).

-1-胺（30.0 mg，73.1 µmol，1.00當量）及

啉（12.7 mg，146 µmol，12.9 µL，2.00當量）於二

烷（1.00 mL）中之溶液中添加Pd₂ (dba)₃ （6.70 mg，7.31 µmol，0.10當量）、RuPhos（6.82 mg，14.6 µmol，0.20當量）及碳酸銫（47.7 mg，146 µmol，2.00當量）。將反應混合物在氮氣氛圍下在110℃下攪拌1小時。將反應混合物冷卻至25℃，過濾，且真空濃縮，得到殘餘物。將殘餘物藉由製備型TLC（二氯甲烷/甲醇＝10/1）純化，得到粗產物，將粗產物藉由製備型HPLC（管柱：Waters Xbridge C18 150×50 mm×10 um；移動相：[A：水（10 mM NH₄ HCO₃ ），B：ACN]；B%：40%-70%）純化，得到呈白色固體狀之(R )-N -(1-(2-甲基-3-(三氟甲基)苯基)乙基)-7-

啉基呔

-1-胺（11.0 mg，26.2 µmol，35.8%產率，99.2%純度）。LCMS [M+1]: 417.1。Step B: Under a nitrogen atmosphere, add ( R )-7-bromo- N -(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)

-1-amine (30.0 mg, 73.1 µmol, 1.00 equivalent) and

Morpholine (12.7 mg, 146 µmol, 12.9 µL, 2.00 equivalent) in two

_{Add Pd 2} (dba) ₃ (6.70 mg, 7.31 µmol, 0.10 equivalent), RuPhos (6.82 mg, 14.6 µmol, 0.20 equivalent) and cesium carbonate (47.7 mg, 146 µmol, 2.00 equivalent) to the solution in alkane (1.00 mL) ). The reaction mixture was stirred at 110°C for 1 hour under a nitrogen atmosphere. The reaction mixture was cooled to 25°C, filtered, and concentrated in vacuo to give a residue. The residue was purified by preparative TLC (dichloromethane/methanol=10/1) to obtain a crude product, and the crude product was subjected to preparative HPLC (column: Waters Xbridge C18 150×50 mm×10 um; mobile phase : [A: water (10 mM NH ₄ HCO ₃ ), B: ACN]; B%: 40%-70%) purified to obtain ( R ) -N -(1-(2-methyl) as a white solid -3-(Trifluoromethyl)phenyl)ethyl)-7-

Linyl

-1-amine (11.0 mg, 26.2 µmol, 35.8% yield, 99.2% purity). LCMS [M+1]: 417.1.

¹ H NMR (400 MHz, CD ₃ OD) δ = 8.56 (s, 1H), 7.79-7.75 (m, 1H), 7.72 (d, J = 8.0 Hz, 1H), 7.62-7.57 (m, 2H), 7.49 (d, J = 7.2 Hz, 1H), 7.25 (t, J = 7.6 Hz, 1H), 5.77 (q, J = 6.8 Hz, 1H), 3.94-3.84 (m, 4H), 3.51-3.42 (m , 4H), 2.61 (s, 3H), 1.64 (d, J = 7.2 Hz, 3H).

(R )-1-(4-(((R )-1-(2-甲基-3-(三氟甲基)苯基)乙基)胺基)呔

-6-基)吡咯啶-3-醇 ¹ H NMR (400 MHz, CD₃ OD) δ 8.69 (s, 1H), 7.89 (br d,J = 8.0 Hz, 1H), 7.71 (br d,J = 7.6 Hz, 1H), 7.52 (br d,J =7.6 Hz, 1H), 7.38 - 7.30 (m, 2H), 7.30 - 7.23 (m, 1H), 5.69 - 5.58 (m, 1H), 4.64 (br s, 1H), 3.76 - 3.63 (m, 3H), 3.52 (br d,J = 11.2 Hz, 1H), 2.61 (s, 3H), 2.30 - 2.11 (m, 2H), 1.67 (br d,J = 6.4 Hz, 3H)。LCMS [M+1]: 417.0。 1-6

7-((1R ,5R )-2,6-二氮雜雙環[3.2.0]庚-2-基)-N -((R )-1-(2-甲基-3-(三氟甲基)苯基)乙基)呔

-1-胺 ¹ H NMR (400 MHz, CD₃ OD) δ = 8.67 (s, 1H), 7.88 (d,J = 8.8 Hz, 1H), 7.74 (d,J = 8.0 Hz, 1H), 7.52 (d,J =8.0 Hz, 1H), 7.41 (d,J = 1.6 Hz, 1H), 7.34 (dd,J = 2.0, 8.8 Hz, 1H), 7.30 - 7.24 (m, 1H), 5.72 (q,J = 6.8 Hz, 1H), 5.19 (t,J =6.0 Hz, 1H), 4.98 - 4.93 (m, 1H), 4.36 (dd,J = 5.6, 10.8 Hz, 1H), 4.23 - 4.17 (m, 1H), 3.93 - 3.85 (m, 1H), 3.49 (dd,J =2.8, 10.4 Hz, 1H), 2.61 (s, 3H), 2.51 - 2.35 (m, 2H), 1.67 (d,J = 6.8 Hz, 3H)。LCMS [M+1]: 428.0。 1-7

(R )-N -(1-(2-甲基-3-(三氟甲基)苯基)乙基)-7-(哌

-1-基)呔

-1-胺 ¹ H NMR (400 MHz, CD₃ OD) δ 8.57 (s, 1H), 7.77 (d,J =10.0 Hz, 1H), 7.73 (d,J =7.6 Hz, 1H), 7.63 - 7.57 (m, 2H), 7.51 (d,J =7.6 Hz, 1H), 7.26 (t,J =7.6 Hz, 1H), 5.78 (q,J =7.2 Hz, 1H), 3.56 - 3.44 (m, 4H), 3.11 - 2.97 (m, 4H), 2.63 (s, 3H), 1.66 (d,J =6.8 Hz, 3H)。LCMS [M+1]: 416.2。 1-8

7-((1R ,5R )-2,6-二氮雜雙環[3.2.0]庚-6-基)-N -((R )-1-(2-甲基-3-(三氟甲基)苯基)乙基)呔

-1-胺 ¹ H NMR (400 MHz, CD₃ OD) δ 8.48 (s, 1H), 7.73 - 7.66 (m, 2H), 7.51 - 7.46 (m, 1H), 7.27 - 7.21 (m, 1H), 7.10 - 7.07 (m, 1H), 7.06 - 7.00 (m, 1H), 5.74 (q,J = 6.9 Hz, 1H), 4.95 - 4.90 (m, 1H), 4.28 - 4.15 (m, 2H), 3.82 - 3.76 (m, 1H), 3.36 - 3.32f (m, 1H), 3.16 - 3.06 (m, 1H), 2.60 (s, 3H), 2.28 - 2.19 (m, 1H), 1.67 - 1.56 (m, 4H)。LCMS [M+1]: 428.0。 1-9

(S )-1-(4-(((R )-1-(2-甲基-3-(三氟甲基)苯基)乙基)胺基)呔

-6-基)吡咯啶-3-醇 ¹ H NMR (400 MHz, CD₃ OD) δ 8.48 (s, 1H), 7.75 - 7.67 (m, 2H), 7.51 - 7.46 (m, 1H), 7.27 - 7.18 (m, 2H), 7.17 - 7.14 (m, 1H), 5.76 (q,J = 6.9 Hz, 1H), 4.65 - 4.59 (m, 1H), 3.72 - 3.54 (m, 3H), 3.48 - 3.41 (m, 1H), 2.61 (s, 3H), 2.29 - 2.06 (m, 2H), 1.64 (d,J = 6.9 Hz, 3H)。LCMS [M+1]: 417.0。 1-10

(R )-N ⁷ ,N ⁷ -二甲基-N ¹ -(1-(4-(2-((甲基胺基)甲基)苯基)噻吩-2-基)乙基)呔

-1,7-二胺 ¹ H NMR (400 MHz, CD₃ OD) δ 8.57 (s, 1H), 7.75 (d,J = 9.0 Hz, 1H), 7.42 - 7.36 (m, 2H), 7.33 - 7.26 (m, 3H), 7.24 - 7.22 (m, 1H), 7.17 - 7.13 (m, 2H), 5.95 - 5.89 (m, 1H), 3.72 (s, 2H), 3.17 (s, 6H), 2.21 (s, 3H), 1.82 (d,J = 6.9 Hz, 3H)。LCMS [M+1]: 418.2。 1-11

(R )-N -(1-(4-(2-((甲基胺基)甲基)苯基)噻吩-2-基)乙基)呔

-1-胺 ¹ H NMR (400 MHz, CD₃ OD) δ 8.88 (s, 1H), 8.37 - 8.33 (m, 1H), 7.97 - 7.90 (m, 3H), 7.44 - 7.40 (m, 1H), 7.36 - 7.28 (m, 3H), 7.20 - 7.16 (m, 2H), 5.96 (q,J = 6.9 Hz, 1H), 3.75 (s, 2H), 2.24 (s, 3H), 1.83 (d,J = 6.9 Hz, 3H)。LCMS [M+1]: 375.1。 1-12

(R )-6,7-二甲氧基-N -(1-(間甲苯基)乙基)呔

-1-胺 ¹ H NMR (400 MHz, CD₃ OD) δ 8.65 (s, 1H), 7.77 (s, 1H), 7.34 - 7.13 (m, 4H), 7.04 - 6.98 (m, 1H), 5.52 (q,J = 7.0 Hz, 1H), 4.06 (s, 3H), 4.00 (s, 3H), 2.31 (s, 3H), 1.67 (d,J = 7.0 Hz, 3H)。LCMS [M+1]: 324.2 1-13

(R )-6,7-二甲氧基-N -(1-(2-甲基-3-(三氟甲基)苯基)乙基)呔

-1-胺 ¹ H NMR (400 MHz, CDCl₃ ) δ 8.81 (s, 1H), 7.67 (d,J = 7.9 Hz, 1H), 7.55 (d,J = 7.9 Hz, 1H), 7.29 - 7.22 (m, 1H), 7.08 (s, 1H), 6.94 (s, 1H), 6.00 - 5.93 (m, 1H), 4.94 (d,J = 6.7 Hz, 1H), 4.04 (s, 3H), 4.02 (s, 3H), 2.56 (s, 3H), 1.68 (d,J = 6.7 Hz, 3H)。LCMS [M+1]: 392.1。 1-14

(R )-6,7-二甲氧基-N -(1-(4-(2-((甲基胺基)甲基)苯基)噻吩-2-基)乙基)呔

-1-胺 ¹ H NMR (400 MHz, CDCl₃ ) δ 8.86 (s, 1H), 7.43 - 7.39 (m, 1H), 7.36 - 7.26 (m, 4H), 7.10 (s, 1H), 6.94 (s, 1H), 6.16 - 6.08 (m, 1H), 5.02 (d,J = 7.9 Hz, 1H), 4.06 (s, 3H), 4.05 (s, 4H), 3.73 (s, 2H), 2.38 (s, 3H), 1.84 (d,J = 6.6 Hz, 3H)。LCMS [M+1]: 435.2。 1-15

N -(1-(5-(2-((甲基胺基)甲基)苯基)噻吩-2-基)乙基)-7-

啉基呔

-1-胺 ¹ H NMR (400 MHz, CD₃ OD) δ 8.64 (s, 1H), 7.79 (d,J = 9.2 Hz, 1H), 7.59 (dd,J = 2.0, 8.8 Hz, 1H), 7.52 (d,J = 1.6 Hz, 1H), 7.41 (d,J = 7.2 Hz, 1H), 7.36 - 7.22 (m, 3H), 7.08 (d,J = 3.6 Hz, 1H), 6.92 (d,J = 3.6 Hz, 1H), 5.92 (q,J = 6.8 Hz, 1H), 3.94 - 3.83 (m, 4H), 3.77 (s, 2H), 3.50 - 3.38 (m, 4H), 2.24 (s, 3H), 1.81 (d,J = 7.2 Hz, 3H)。LCMS [M+1]: 460.2。 1-16

(R )-4-(4-((1-(5-(2-((甲基胺基)甲基)苯基)噻吩-2-基)乙基)胺基)呔

-6-基)哌

-2-酮 ¹ H NMR (400 MHz, CD₃ OD) δ  9.00 (s, 1H), 8.14 (d,J = 9.2 Hz, 1H), 7.76 (dd,J = 2.4, 9.6 Hz, 1H), 7.65 (s, 1H), 7.60 - 7.54 (m, 1H), 7.53 - 7.43 (m, 3H), 7.21 (d,J = 3.2 Hz, 1H), 7.01 (d,J = 3.6 Hz, 1H), 5.83 - 5.72 (m, 1H), 4.34 (s, 2H), 4.26 (s, 2H), 3.97 - 3.87 (m, 2H), 3.62 - 3.53 (m, 2H), 2.64 (s, 3H), 1.88 (d,J = 6.8 Hz, 3H)。 LCMS [M+1]: 473.2。 1-17

(R )-4-(4-((1-(2-甲基-3-(三氟甲基)苯基)乙基)胺基)呔

-6-基)哌

-2-酮 ¹ H NMR (400 MHz, CD₃ OD) δ  8.93 (s, 1H), 8.10 (d,J = 9.2 Hz, 1H), 7.77 - 7.69 (m, 3H), 7.55 (d,J = 7.6 Hz, 1H), 7.30 (t,J = 8.8 Hz, 1H), 5.62 - 5.55 (m, 1H), 4.30 (s, 2H), 3.97 - 3.91 (m, 2H), 3.61 - 3.55 (m, 2H), 2.62 (s, 3H), 1.70 (d,J = 6.8 Hz, 3H)。LCMS [M+1]: 430.3。 1-18

(R )-N -(1-(5-(2-((甲基胺基)甲基)苯基)噻吩-2-基)乙基)-7-

啉基呔

-1-胺 ¹ H NMR (400 MHz, CD₃ OD) δ  8.64 (s, 1H), 7.80 (d,J = 8.8 Hz, 1H), 7.66 - 7.56 (m, 1H), 7.52 (s, 1H), 7.46 - 7.38 (m, 1H), 7.37 - 7.21 (m, 3H), 7.09 (d,J = 2.8 Hz, 1H), 6.92 (d,J = 2.8 Hz, 1H), 6.02 - 5.85 (m, 1H), 3.91 - 3.83 (m, 4H), 3.78 (s, 2H), 3.47 - 3.40 (m, 4H), 2.24 (s, 3H), 1.81 (d,J = 6.8 Hz, 3H)。LCMS [M+1]: 460.2。 1-19

(R )-N ⁷ ,N ⁷ -二甲基-N ¹ -(1-(5-(2-((甲基胺基)甲基)苯基)噻吩-2-基)乙基)呔

-1,7-二胺 ¹ H NMR (400 MHz, CD₃ OD) δ = 8.92 (br s, 1H), 8.05 (d,J = 9.2 Hz, 1H), 7.59 - 7.53 (m, 2H), 7.52 - 7.43 (m, 4H), 7.19 (d,J = 3.2 Hz, 1H), 7.00 (d,J = 3.6 Hz, 1H), 5.82 - 5.71 (m, 1H), 4.34 (s, 2H), 3.30 (s, 6H), 2.63 (s, 3H), 1.86 (d,J = 6.8 Hz, 3H)。LCMS [M+1]: 418.2。 1-20

(R )-1-(4-((1-(4-(2-((甲基胺基)甲基)苯基)噻吩-2-基)乙基)胺基)呔

-6-基)哌

-2-酮 ¹ H NMR (400 MHz, CD₃ OD) δ = 9.10 (s, 1H), 8.79 (d,J = 3.2 Hz, 1H), 8.31 - 8.27 (m, 1H), 8.27 - 8.22 (m, 1H), 7.58 - 7.53 (m, 1H), 7.49 - 7.44 (m, 2H), 7.42 - 7.39 (m, 1H), 7.37 (d,J = 1.2 Hz, 1H), 7.28 (s, 1H), 5.79 - 5.71 (m, 1H), 4.26 (s, 2H), 4.24 - 4.18 (m, 2H), 4.12 (s, 2H), 3.79 - 3.73 (m, 2H), 2.59 (s, 3H), 1.92 (d,J = 6.8 Hz, 3H); LCMS [M+1]: 473.4。 1-21

(R )-N -(1-(2-甲基-3-(三氟甲基)苯基)乙基)-7-(4-甲基哌

-1-基)呔

-1-胺 ¹ H NMR (400 MHz, CD₃ OD) δ = 8.55 (s, 1H), 7.75 (d,J = 9.6 Hz, 1H), 7.71 (d,J =8.0 Hz, 1H), 7.61 - 7.55 (m, 2H), 7.49 (d,J = 7.2 Hz, 1H), 7.24 (t,J = 8.0 Hz, 1H), 5.76 (q,J = 6.8 Hz, 1H), 3.61 - 3.46 (m, 4H), 2.72 - 2.63 (m, 4H), 2.61 (s, 3H), 2.39 (s, 3H), 1.64 (d,J = 6.8 Hz, 3H)。LCMS [M+1]: 430.2。 1-22

7-((1S ,5S )-2,6-二氮雜雙環[3.2.0]庚-6-基)-N -((R )-1-(2-甲基-3-(三氟甲基)苯基)乙基)呔

-1-胺 ¹ H NMR (400 MHz, CD₃ OD) δ = 8.59 (s, 1H), 7.78 (d,J = 8.8 Hz, 1H), 7.70 (d,J = 7.6 Hz, 1H), 7.51 (d,J = 8.0 Hz, 1H), 7.25 (t,J = 8.0 Hz, 1H), 7.18 (d,J = 2.0 Hz, 1H), 7.10 (dd,J = 2.4, 8.8 Hz, 1H), 5.68 (q,J = 6.8 Hz, 1H), 4.99 (t,J = 4.8 Hz, 1H), 4.35 - 4.29 (m, 1H), 4.28 - 4.22 (m, 1H), 3.85 (dd,J = 2.8, 9.2 Hz, 1H), 3.38 (dd,J = 6.8, 11.6 Hz, 1H), 3.21 - 3.09 (m, 1H), 2.60 (s, 3H), 2.27 (dd,J = 5.2, 13.6 Hz, 1H), 1.73 - 1.67 (m, 1H), 1.65 (d,J = 6.8 Hz, 3H)。LCMS [M+1]⁺ : 428.0。 1-23

N -(1-(5-(2-((二甲基胺基)甲基)苯基)噻吩-2-基)乙基)-7-

啉基呔

-1-胺 ¹ H NMR (400 MHz, CDCl₃ ) δ = 11.63 (s, 1H), 8.84 - 8.83 (m, 2H), 7.98 (s, 1H), 7.75 (d,J = 9.2 Hz, 1H), 7.46 - 7.39 (m, 5H), 7.08 (d,J = 3.6 Hz, 1H), 6.86 (d,J = 3.6 Hz, 1H), 5.66 - 5.63 (m, 1H), 4.72 (d,J = 13.6 Hz, 1H), 4.27 (d,J = 13.6 Hz, 1H), 3.82 (t,J = 4.8 Hz, 3H), 3.55 (t,J = 4.8 Hz, 3H), 2.68 - 2.64 (m, 6H), 1.77 (d,J = 6.8 Hz, 3H)。LCMS [M+1]: 474.2。 1-24

(R )-N ,N -二甲基-1-(4-((1-(2-甲基-3-(三氟甲基)苯基)乙基)胺基)呔

-6-基)氮雜環丁烷-3-羧醯胺 LCMS [M+1]: 458.0。 1-25

(R )-7-(5,6-二氫-[1,2,4]三唑并[1,5-a]吡

-7(8H )-基)-N -(1-(2-甲基-3-(三氟甲基)苯基)乙基)呔

-1-胺 LCMS [M+1]: 454.2。 1-26

1,5-二甲基-4-(4-(((R )-1-(2-甲基-3-(三氟甲基)苯基)乙基)胺基)呔

-6-基)哌

-2-酮 LCMS [M+1]: 458.2。 1-27

N -((R )-1-(2-甲基-3-(三氟甲基)苯基)乙基)-7-(3-甲基

啉基)呔

-1-胺 LCMS [M+1]: 431.2。 1-28

(R )-7-(2,3-二甲基-5,6-二氫咪唑并[1,2-a ]吡

-7(8H )-基)-N -(1-(2-甲基-3-(三氟甲基)苯基)乙基)呔

-1-胺 LCMS [M+1]: 481.2。 1-29

(R )-7-(4-甲基-1,4-二氮雜環庚烷-1-基)-N -(1-(2-甲基-3-(三氟甲基)苯基)乙基)呔

-1-胺 LCMS [M+1]: 441.1。 1-30

(R )-1-甲基-4-(4-((1-(2-甲基-3-(三氟甲基)苯基)乙基)胺基)呔

-6-基)哌

-2-酮 LCMS [M+1]: 444.0。 1-31

N -((R )-1-(2-甲基-3-(三氟甲基)苯基)乙基)-7-(5-甲基八氫-2H -吡咯并[3,4-c ]吡啶-2-基)呔

-1-胺 LCMS [M+1]: 471.2。 1-32

(R )-7-(6-(二甲基胺基)-2-氮雜螺[3.3]庚-2-基)-N -(1-(2-甲基-3-(三氟甲基)苯基)乙基)呔

-1-胺 LCMS [M+1]: 470.2。 1-33

N -((R )-1-(2-甲基-3-(三氟甲基)苯基)乙基)-7-(1-甲基八氫-6H -吡咯并[2,3-c ]吡啶-6-基)呔

-1-胺 LCMS [M+1]: 470.1。 1-34

N -((R )-1-(2-甲基-3-(三氟甲基)苯基)乙基)-7-(7-甲基-2,7-二氮雜螺[4.5]癸-2-基)呔

-1-胺 LCMS [M+1]: 485.2。 1-35

N -((R )-1-(2-甲基-3-(三氟甲基)苯基)乙基)-7-(1-甲基八氫-5H -吡咯并[3,2-c ]吡啶-5-基)呔

-1-胺 LCMS [M+1]: 471.2。 1-36

7-(3-(二甲基胺基)哌啶-1-基)-N -((R )-1-(2-甲基-3-(三氟甲基)苯基)乙基)呔

-1-胺 LCMS [M+1]: 458.2。 1-37

(R )-N -(1-(2-甲基-3-(三氟甲基)苯基)乙基)-7-(3-甲基-5,6-二氫咪唑并[1,5-a ]吡

-7(8H )-基)呔

-1-胺 LCMS [M+1]: 467.2。 1-38

N -((R )-1-(2-甲基-3-(三氟甲基)苯基)乙基)-7-(4-甲基八氫-1H -吡咯并[3,2-b ]吡啶-1-基)呔

-1-胺 LCMS [M+1]: 470.2。 1-39

N -((R )-1-(2-甲基-3-(三氟甲基)苯基)乙基)-7-(7-甲基-2,7-二氮雜螺[4.4]壬-2-基)呔

-1-胺 LCMS [M+1]: 470.4。 1-40

(R )-N -(1-(2-甲基-3-(三氟甲基)苯基)乙基)-7-(2-甲基-5,6-二氫咪唑并[1,2-a ]吡

-7(8H )-基)呔

-1-胺 LCMS [M+1]: 467.2。 1-41

N -((R )-1-(2-甲基-3-(三氟甲基)苯基)乙基)-7-(2,6-二氧雜-9-氮雜螺[4.5]癸-9-基)呔

-1-胺 LCMS [M+1]: 473.0。 1-42

N -((R )-1-(2-甲基-3-(三氟甲基)苯基)乙基)-7-(1-甲基八氫-1,6-

啶-6(2H )-基)呔

-1-胺 LCMS [M+1]: 485.2。 1-43

7-(3-(氟甲基)-4-甲基哌

-1-基)-N -((R )-1-(2-甲基-3-(三氟甲基)苯基)乙基)呔

-1-胺 LCMS [M+1]: 462.1。 1-44

7-(2,8-二甲基-5,6-二氫咪唑并[1,2-a ]吡

-7(8H )-基)-N -((R )-1-(2-甲基-3-(三氟甲基)苯基)乙基)呔

-1-胺 LCMS [M+1]: 481.2。 1-45

(R )-7-(3,4,6,7,8,9-六氫苯并[4,5]咪唑并[1,2-a ]吡

-2(1H )-基)-N -(1-(2-甲基-3-(三氟甲基)苯基)乙基)呔

-1-胺 LCMS [M+1]: 508.2。 1-46

(R )-7-(3,4-二氫苯并[4,5]咪唑并[1,2-a]吡

-2(1H )-基)-N -(1-(2-甲基-3-(三氟甲基)苯基)乙基)呔

-1-胺 LCMS [M+1]: 503.2。 1-47

7-(8-甲基-2-(三氟甲基)-5,6-二氫咪唑并[1,2-a]吡

-7(8H )-基)-N -((R )-1-(2-甲基-3-(三氟甲基)苯基)乙基)呔

-1-胺 LCMS [M+1]: 535.0。 1-48

(R )-7-(5,6-二氫咪唑并[1,5-a ]吡

-7(8H )-基)-N -(1-(2-甲基-3-(三氟甲基)苯基)乙基)呔

-1-胺 LCMS [M+1]: 453.2。 1-49

7-(3-(氮雜環丁烷-1-基)哌啶-1-基)-N -((R )-1-(2-甲基-3-(三氟甲基)苯基)乙基)呔

-1-胺 LCMS [M+1]: 470.2。 1-50

7-(3-(二甲基胺基)氮雜環庚烷-1-基)-N -((R )-1-(2-甲基-3-(三氟甲基)苯基)乙基)呔

-1-胺 LCMS [M+1]: 472.2。 實例2-1 (R )-N -(1-(4-(2-((二甲基胺基)甲基)苯基)噻吩-2-基)乙基)-7-

啉基呔

-1-胺

Following the teaching of general reaction scheme III and the procedure of preparation examples 1-1-1-4, the following compounds of formula (I) as shown in Table 1, examples 1-5 to 1-50 were prepared: Table 1 Example # structure Spectral data 1-5

( R )-1-(4-((( R )-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)

-6-yl)pyrrolidin-3-ol ¹ H NMR (400 MHz, CD ₃ OD) δ 8.69 (s, 1H), 7.89 (br d, J = 8.0 Hz, 1H), 7.71 (br d, J = 7.6 Hz, 1H), 7.52 (br d, J =7.6 Hz, 1H), 7.38-7.30 (m, 2H), 7.30-7.23 (m, 1H), 5.69-5.58 (m, 1H), 4.64 (br s, 1H), 3.76-3.63 (m, 3H) ), 3.52 (br d, J = 11.2 Hz, 1H), 2.61 (s, 3H), 2.30-2.11 (m, 2H), 1.67 (br d, J = 6.4 Hz, 3H). LCMS [M+1]: 417.0. 1-6

7-((1 R ,5 R )-2,6-diazabicyclo[3.2.0]heptan-2-yl)- N -(( R )-1-(2-methyl-3-(三(Fluoromethyl)phenyl)ethyl)

-1-amine ¹ H NMR (400 MHz, CD ₃ OD) δ = 8.67 (s, 1H), 7.88 (d, J = 8.8 Hz, 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.52 (d, J = 8.0 Hz, 1H), 7.41 (d, J = 1.6 Hz, 1H), 7.34 (dd, J = 2.0, 8.8 Hz, 1H), 7.30-7.24 (m, 1H), 5.72 (q, J = 6.8 Hz, 1H), 5.19 (t, J = 6.0 Hz, 1H), 4.98-4.93 (m, 1H), 4.36 (dd, J = 5.6, 10.8 Hz, 1H), 4.23-4.17 (m, 1H), 3.93-3.85 (m, 1H), 3.49 (dd, J =2.8, 10.4 Hz, 1H), 2.61 (s, 3H), 2.51-2.35 (m, 2H), 1.67 (d, J = 6.8 Hz, 3H). LCMS [M+1]: 428.0. 1-7

( R ) -N -(1-(2-Methyl-3-(trifluoromethyl)phenyl)ethyl)-7-(piper

-1-base) 呔

-1-amine ¹ H NMR (400 MHz, CD ₃ OD) δ 8.57 (s, 1H), 7.77 (d, J =10.0 Hz, 1H), 7.73 (d, J =7.6 Hz, 1H), 7.63-7.57 (m, 2H ), 7.51 (d, J =7.6 Hz, 1H), 7.26 (t, J =7.6 Hz, 1H), 5.78 (q, J =7.2 Hz, 1H), 3.56-3.44 (m, 4H), 3.11-2.97 (m, 4H), 2.63 (s, 3H), 1.66 (d, J =6.8 Hz, 3H). LCMS [M+1]: 416.2. 1-8

7-((1 R ,5 R )-2,6-diazabicyclo[3.2.0]heptan-6-yl) -N -(( R )-1-(2-methyl-3-(三(Fluoromethyl)phenyl)ethyl)

-1-amine ¹ H NMR (400 MHz, CD ₃ OD) δ 8.48 (s, 1H), 7.73-7.66 (m, 2H), 7.51-7.46 (m, 1H), 7.27-7.21 (m, 1H), 7.10-7.07 ( m, 1H), 7.06-7.00 (m, 1H), 5.74 (q, J = 6.9 Hz, 1H), 4.95-4.90 (m, 1H), 4.28-4.15 (m, 2H), 3.82-3.76 (m, 1H), 3.36-3.32f (m, 1H), 3.16-3.06 (m, 1H), 2.60 (s, 3H), 2.28-2.19 (m, 1H), 1.67-1.56 (m, 4H). LCMS [M+1]: 428.0. 1-9

( S )-1-(4-((( R )-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)

-6-yl)pyrrolidin-3-ol ¹ H NMR (400 MHz, CD ₃ OD) δ 8.48 (s, 1H), 7.75-7.67 (m, 2H), 7.51-7.46 (m, 1H), 7.27-7.18 (m, 2H), 7.17-7.14 ( m, 1H), 5.76 (q, J = 6.9 Hz, 1H), 4.65-4.59 (m, 1H), 3.72-3.54 (m, 3H), 3.48-3.41 (m, 1H), 2.61 (s, 3H) , 2.29-2.06 (m, 2H), 1.64 (d, J = 6.9 Hz, 3H). LCMS [M+1]: 417.0. 1-10

( R )- N ⁷ , N ⁷ -Dimethyl- N ¹ -(1-(4-(2-((methylamino)methyl)phenyl)thiophen-2-yl)ethyl)

-1,7-diamine ¹ H NMR (400 MHz, CD ₃ OD) δ 8.57 (s, 1H), 7.75 (d, J = 9.0 Hz, 1H), 7.42-7.36 (m, 2H), 7.33-7.26 (m, 3H), 7.24 -7.22 (m, 1H), 7.17-7.13 (m, 2H), 5.95-5.89 (m, 1H), 3.72 (s, 2H), 3.17 (s, 6H), 2.21 (s, 3H), 1.82 (d , J = 6.9 Hz, 3H). LCMS [M+1]: 418.2. 1-11

( R ) -N -(1-(4-(2-((methylamino)methyl)phenyl)thiophen-2-yl)ethyl)

-1-amine ¹ H NMR (400 MHz, CD ₃ OD) δ 8.88 (s, 1H), 8.37-8.33 (m, 1H), 7.97-7.90 (m, 3H), 7.44-7.40 (m, 1H), 7.36-7.28 ( m, 3H), 7.20-7.16 (m, 2H), 5.96 (q, J = 6.9 Hz, 1H), 3.75 (s, 2H), 2.24 (s, 3H), 1.83 (d, J = 6.9 Hz, 3H ). LCMS [M+1]: 375.1. 1-12

( R )-6,7-Dimethoxy- N -(1-(m-tolyl)ethyl)

-1-amine ¹ H NMR (400 MHz, CD ₃ OD) δ 8.65 (s, 1H), 7.77 (s, 1H), 7.34-7.13 (m, 4H), 7.04-6.98 (m, 1H), 5.52 (q, J = 7.0 Hz, 1H), 4.06 (s, 3H), 4.00 (s, 3H), 2.31 (s, 3H), 1.67 (d, J = 7.0 Hz, 3H). LCMS [M+1]: 324.2 1-13

( R )-6,7-Dimethoxy- N -(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)

-1-amine ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.81 (s, 1H), 7.67 (d, J = 7.9 Hz, 1H), 7.55 (d, J = 7.9 Hz, 1H), 7.29-7.22 (m, 1H) , 7.08 (s, 1H), 6.94 (s, 1H), 6.00-5.93 (m, 1H), 4.94 (d, J = 6.7 Hz, 1H), 4.04 (s, 3H), 4.02 (s, 3H), 2.56 (s, 3H), 1.68 (d, J = 6.7 Hz, 3H). LCMS [M+1]: 392.1. 1-14

( R )-6,7-Dimethoxy- N -(1-(4-(2-((methylamino)methyl)phenyl)thiophen-2-yl)ethyl)

-1-amine ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.86 (s, 1H), 7.43-7.39 (m, 1H), 7.36-7.26 (m, 4H), 7.10 (s, 1H), 6.94 (s, 1H), 6.16-6.08 (m, 1H), 5.02 (d, J = 7.9 Hz, 1H), 4.06 (s, 3H), 4.05 (s, 4H), 3.73 (s, 2H), 2.38 (s, 3H), 1.84 (d, J = 6.6 Hz, 3H). LCMS [M+1]: 435.2. 1-15

N -(1-(5-(2-((methylamino)methyl)phenyl)thiophen-2-yl)ethyl)-7-

Linyl

-1-amine ¹ H NMR (400 MHz, CD ₃ OD) δ 8.64 (s, 1H), 7.79 (d, J = 9.2 Hz, 1H), 7.59 (dd, J = 2.0, 8.8 Hz, 1H), 7.52 (d, J = 1.6 Hz, 1H), 7.41 (d, J = 7.2 Hz, 1H), 7.36-7.22 (m, 3H), 7.08 (d, J = 3.6 Hz, 1H), 6.92 (d, J = 3.6 Hz, 1H ), 5.92 (q, J = 6.8 Hz, 1H), 3.94-3.83 (m, 4H), 3.77 (s, 2H), 3.50-3.38 (m, 4H), 2.24 (s, 3H), 1.81 (d, J = 7.2 Hz, 3H). LCMS [M+1]: 460.2. 1-16

( R )-4-(4-((1-(5-(2-((methylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino)

-6-yl)piperidine

-2-one ¹ H NMR (400 MHz, CD ₃ OD) δ 9.00 (s, 1H), 8.14 (d, J = 9.2 Hz, 1H), 7.76 (dd, J = 2.4, 9.6 Hz, 1H), 7.65 (s, 1H ), 7.60-7.54 (m, 1H), 7.53-7.43 (m, 3H), 7.21 (d, J = 3.2 Hz, 1H), 7.01 (d, J = 3.6 Hz, 1H), 5.83-5.72 (m, 1H), 4.34 (s, 2H), 4.26 (s, 2H), 3.97-3.87 (m, 2H), 3.62-3.53 (m, 2H), 2.64 (s, 3H), 1.88 (d, J = 6.8 Hz , 3H). LCMS [M+1]: 473.2. 1-17

( R )-4-(4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)

-6-yl)piperidine

-2-one ¹ H NMR (400 MHz, CD ₃ OD) δ 8.93 (s, 1H), 8.10 (d, J = 9.2 Hz, 1H), 7.77-7.69 (m, 3H), 7.55 (d, J = 7.6 Hz, 1H ), 7.30 (t, J = 8.8 Hz, 1H), 5.62-5.55 (m, 1H), 4.30 (s, 2H), 3.97-3.91 (m, 2H), 3.61-3.55 (m, 2H), 2.62 ( s, 3H), 1.70 (d, J = 6.8 Hz, 3H). LCMS [M+1]: 430.3. 1-18

( R ) -N -(1-(5-(2-((Methylamino)methyl)phenyl)thiophen-2-yl)ethyl)-7-

Linyl

-1-amine ¹ H NMR (400 MHz, CD ₃ OD) δ 8.64 (s, 1H), 7.80 (d, J = 8.8 Hz, 1H), 7.66-7.56 (m, 1H), 7.52 (s, 1H), 7.46-7.38 (m, 1H), 7.37-7.21 (m, 3H), 7.09 (d, J = 2.8 Hz, 1H), 6.92 (d, J = 2.8 Hz, 1H), 6.02-5.85 (m, 1H), 3.91- 3.83 (m, 4H), 3.78 (s, 2H), 3.47-3.40 (m, 4H), 2.24 (s, 3H), 1.81 (d, J = 6.8 Hz, 3H). LCMS [M+1]: 460.2. 1-19

( R )- N ⁷ , N ⁷ -Dimethyl- N ¹ -(1-(5-(2-((methylamino)methyl)phenyl)thiophen-2-yl)ethyl)

-1,7-diamine ¹ H NMR (400 MHz, CD ₃ OD) δ = 8.92 (br s, 1H), 8.05 (d, J = 9.2 Hz, 1H), 7.59-7.53 (m, 2H), 7.52-7.43 (m, 4H) , 7.19 (d, J = 3.2 Hz, 1H), 7.00 (d, J = 3.6 Hz, 1H), 5.82-5.71 (m, 1H), 4.34 (s, 2H), 3.30 (s, 6H), 2.63 ( s, 3H), 1.86 (d, J = 6.8 Hz, 3H). LCMS [M+1]: 418.2. 1-20

( R )-1-(4-((1-(4-(2-((methylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino)

-6-yl)piperidine

-2-one ¹ H NMR (400 MHz, CD ₃ OD) δ = 9.10 (s, 1H), 8.79 (d, J = 3.2 Hz, 1H), 8.31-8.27 (m, 1H), 8.27-8.22 (m, 1H), 7.58-7.53 (m, 1H), 7.49-7.44 (m, 2H), 7.42-7.39 (m, 1H), 7.37 (d, J = 1.2 Hz, 1H), 7.28 (s, 1H), 5.79-5.71 ( m, 1H), 4.26 (s, 2H), 4.24-4.18 (m, 2H), 4.12 (s, 2H), 3.79-3.73 (m, 2H), 2.59 (s, 3H), 1.92 (d, J = 6.8 Hz, 3H); LCMS [M+1]: 473.4. 1-21

( R ) -N -(1-(2-Methyl-3-(trifluoromethyl)phenyl)ethyl)-7-(4-methylpiper

-1-base) 呔

-1-amine ¹ H NMR (400 MHz, CD ₃ OD) δ = 8.55 (s, 1H), 7.75 (d, J = 9.6 Hz, 1H), 7.71 (d, J =8.0 Hz, 1H), 7.61-7.55 (m, 2H), 7.49 (d, J = 7.2 Hz, 1H), 7.24 (t, J = 8.0 Hz, 1H), 5.76 (q, J = 6.8 Hz, 1H), 3.61-3.46 (m, 4H), 2.72- 2.63 (m, 4H), 2.61 (s, 3H), 2.39 (s, 3H), 1.64 (d, J = 6.8 Hz, 3H). LCMS [M+1]: 430.2. 1-22

7-((1 S ,5 S )-2,6-diazabicyclo[3.2.0]heptan-6-yl) -N -(( R )-1-(2-methyl-3-(三(Fluoromethyl)phenyl)ethyl)

-1-amine ¹ H NMR (400 MHz, CD ₃ OD) δ = 8.59 (s, 1H), 7.78 (d, J = 8.8 Hz, 1H), 7.70 (d, J = 7.6 Hz, 1H), 7.51 (d, J = 8.0 Hz, 1H), 7.25 (t, J = 8.0 Hz, 1H), 7.18 (d, J = 2.0 Hz, 1H), 7.10 (dd, J = 2.4, 8.8 Hz, 1H), 5.68 (q, J = 6.8 Hz, 1H), 4.99 (t, J = 4.8 Hz, 1H), 4.35-4.29 (m, 1H), 4.28-4.22 (m, 1H), 3.85 (dd, J = 2.8, 9.2 Hz, 1H), 3.38 (dd, J = 6.8, 11.6 Hz, 1H), 3.21-3.09 (m, 1H), 2.60 (s, 3H), 2.27 (dd, J = 5.2, 13.6 Hz, 1H), 1.73-1.67 (m, 1H), 1.65 (d, J = 6.8 Hz, 3H). LCMS [M+1] ⁺ : 428.0. 1-23

N -(1-(5-(2-((dimethylamino)methyl)phenyl)thiophen-2-yl)ethyl)-7-

Linyl

-1-amine ¹ H NMR (400 MHz, CDCl ₃ ) δ = 11.63 (s, 1H), 8.84-8.83 (m, 2H), 7.98 (s, 1H), 7.75 (d, J = 9.2 Hz, 1H), 7.46-7.39 (m, 5H), 7.08 (d, J = 3.6 Hz, 1H), 6.86 (d, J = 3.6 Hz, 1H), 5.66-5.63 (m, 1H), 4.72 (d, J = 13.6 Hz, 1H) , 4.27 (d, J = 13.6 Hz, 1H), 3.82 (t, J = 4.8 Hz, 3H), 3.55 (t, J = 4.8 Hz, 3H), 2.68-2.64 (m, 6H), 1.77 (d, J = 6.8 Hz, 3H). LCMS [M+1]: 474.2. 1-24

( R )- N , N -Dimethyl-1-(4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)

-6-yl)azetidine-3-carboxamide LCMS [M+1]: 458.0. 1-25

( R )-7-(5,6-Dihydro-[1,2,4]triazolo[1,5-a]pyridine

-7(8 H )-yl) -N -(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)

-1-amine LCMS [M+1]: 454.2. 1-26

1,5-Dimethyl-4-(4-((( R )-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)

-6-yl)piperidine

-2-one LCMS [M+1]: 458.2. 1-27

N -(( R )-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-7-(3-methyl

Linyl)

-1-amine LCMS [M+1]: 431.2. 1-28

( R )-7-(2,3-Dimethyl-5,6-dihydroimidazo[1,2- a ]pyridine

-7(8 H )-yl) -N -(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)

-1-amine LCMS [M+1]: 481.2. 1-29

( R )-7-(4-methyl-1,4-diazepan-1-yl) -N -(1-(2-methyl-3-(trifluoromethyl)phenyl) Ethyl)

-1-amine LCMS [M+1]: 441.1. 1-30

( R )-1-methyl-4-(4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)

-6-yl)piperidine

-2-one LCMS [M+1]: 444.0. 1-31

N -(( R )-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-7-(5-methyloctahydro-2 H -pyrrolo[3,4- c )pyridin-2-yl)

-1-amine LCMS [M+1]: 471.2. 1-32

( R )-7-(6-(Dimethylamino)-2-azaspiro[3.3]heptan-2-yl) -N -(1-(2-methyl-3-(trifluoromethyl )Phenyl) ethyl) 呔

-1-amine LCMS [M+1]: 470.2. 1-33

N -(( R )-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-7-(1-methyloctahydro-6 H -pyrrolo[2,3- c ]pyridine-6-yl)

-1-amine LCMS [M+1]: 470.1. 1-34

N -(( R )-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-7-(7-methyl-2,7-diazaspiro[4.5]deca -2-base)

-1-amine LCMS [M+1]: 485.2. 1-35

N -(( R )-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-7-(1-methyloctahydro-5 H -pyrrolo[3,2- c ]pyridin-5-yl)

-1-amine LCMS [M+1]: 471.2. 1-36

7-(3-(Dimethylamino)piperidin-1-yl) -N -(( R )-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)

-1-amine LCMS [M+1]: 458.2. 1-37

( R ) -N -(1-(2-Methyl-3-(trifluoromethyl)phenyl)ethyl)-7-(3-methyl-5,6-dihydroimidazo[1,5 -a ]pyridine

-7(8 H )-基)呔

-1-amine LCMS [M+1]: 467.2. 1-38

N -(( R )-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-7-(4-methyloctahydro-1 H -pyrrolo[3,2- b ]pyridin-1-yl)

-1-amine LCMS [M+1]: 470.2. 1-39

N -(( R )-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-7-(7-methyl-2,7-diazaspiro[4.4]non -2-base)

-1-amine LCMS [M+1]: 470.4. 1-40

( R ) -N -(1-(2-Methyl-3-(trifluoromethyl)phenyl)ethyl)-7-(2-methyl-5,6-dihydroimidazo[1,2 -a ]pyridine

-7(8 H )-基)呔

-1-amine LCMS [M+1]: 467.2. 1-41

N -(( R )-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-7-(2,6-dioxa-9-azaspiro[4.5]deca -9-base) 呔

-1-amine LCMS [M+1]: 473.0. 1-42

N -(( R )-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-7-(1-methyloctahydro-1,6-

Pyridine-6(2 H )-yl)

-1-amine LCMS [M+1]: 485.2. 1-43

7-(3-(fluoromethyl)-4-methylpiper

-1-yl) -N -(( R )-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)

-1-amine LCMS [M+1]: 462.1. 1-44

7-(2,8-Dimethyl-5,6-dihydroimidazo[1,2- a ]pyridine

-7(8 H )-yl) -N -(( R )-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)

-1-amine LCMS [M+1]: 481.2. 1-45

( R )-7-(3,4,6,7,8,9-hexahydrobenzo[4,5]imidazo[1,2- a ]pyridine

-2(1 H )-yl) -N -(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)

-1-amine LCMS [M+1]: 508.2. 1-46

( R )-7-(3,4-Dihydrobenzo[4,5]imidazo[1,2-a]pyridine

-2(1 H )-yl) -N -(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)

-1-amine LCMS [M+1]: 503.2. 1-47

7-(8-Methyl-2-(trifluoromethyl)-5,6-dihydroimidazo[1,2-a]pyridine

-7(8 H )-yl) -N -(( R )-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)

-1-amine LCMS [M+1]: 535.0. 1-48

( R )-7-(5,6-Dihydroimidazo[1,5- a ]pyridine

-7(8 H )-yl) -N -(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)

-1-amine LCMS [M+1]: 453.2. 1-49

7-(3-(azetidin-1-yl)piperidin-1-yl) -N -(( R )-1-(2-methyl-3-(trifluoromethyl)phenyl) Ethyl)

-1-amine LCMS [M+1]: 470.2. 1-50

7-(3-(Dimethylamino)azeppan-1-yl) -N -(( R )-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl Base) eh

-1-amine LCMS [M+1]: 472.2. Example 2-1 ( R ) -N -(1-(4-(2-((dimethylamino)methyl)phenyl)thiophen-2-yl)ethyl)-7-

Linyl

-1-amine

啉基呔

-1-胺（15.0 mg，32.6 µmol，1.00當量）於二甲基甲醯胺（0.50 mL）中之溶液中添加氫氧化鉀（2.75 mg，49.0 µmol，1.50當量），且將反應混合物在15℃下攪拌1小時。將4-甲基苯磺酸甲酯（7.90 mg，42.4 µmol，1.3當量）於二甲基甲醯胺（0.20 mL）中之溶液逐滴添加至反應混合物中。滴加完成後，將反應混合物加熱至50℃且攪拌2小時。隨後將反應混合物冷卻至25℃，且將乙酸乙酯（3.00 mL）及水（3.00 mL）添加至混合物中。分離各層，且將有機相合併，用水（3.00 mL）洗滌兩次，且經無水硫酸鈉乾燥，得到殘餘物。將殘餘物藉由製備型HPLC（管柱：Waters Xbridge 150×25 mm×5 um；移動相：[水（0.05%氫氧化氨v/v）-ACN]；B%：32%-62%，10分鐘）純化，得到呈灰白色固體狀之(R )-N -(1-(4-(2-((二甲基胺基)甲基)苯基)噻吩-2-基)乙基)-7-

啉基呔

-1-胺（1.61 mg，3.39 µmol，10.4%產率，99.7%純度）。LCMS [M+1]: 474.3。At 15 ℃, to ( R ) -N -(1-(4-(2-((methylamino)methyl)phenyl)thiophen-2-yl)ethyl)-7-

Linyl

-1-amine (15.0 mg, 32.6 µmol, 1.00 equivalent) in dimethylformamide (0.50 mL) was added potassium hydroxide (2.75 mg, 49.0 µmol, 1.50 equivalent), and the reaction mixture was heated to 15 Stir at °C for 1 hour. A solution of methyl 4-methylbenzenesulfonate (7.90 mg, 42.4 µmol, 1.3 equivalents) in dimethylformamide (0.20 mL) was added dropwise to the reaction mixture. After completion of the dropwise addition, the reaction mixture was heated to 50°C and stirred for 2 hours. The reaction mixture was then cooled to 25°C, and ethyl acetate (3.00 mL) and water (3.00 mL) were added to the mixture. The layers were separated, and the organic phases were combined, washed twice with water (3.00 mL), and dried over anhydrous sodium sulfate to obtain a residue. The residue was subjected to preparative HPLC (column: Waters Xbridge 150×25 mm×5 um; mobile phase: [water (0.05% ammonium hydroxide v/v)-ACN]; B%: 32%-62%, 10 minutes) Purify to obtain ( R ) -N -(1-(4-(2-((dimethylamino)methyl)phenyl)thiophen-2-yl)ethyl)- as off-white solid 7-

Linyl

-1-amine (1.61 mg, 3.39 µmol, 10.4% yield, 99.7% purity). LCMS [M+1]: 474.3.

-1-胺

¹ H NMR (400 MHz, CD ₃ OD) δ 8.65 (s, 1H), 7.81 (d, J = 8.8 Hz, 1H), 7.61 (dd, J = 2.4, 9.2 Hz, 1H), 7.54 (d, J = 2.4 Hz, 1H), 7.48-7.41 (m, 1H), 7.37-7.29 (m, 3H), 7.21 (d, J = 1.2 Hz, 1H), 7.18-7.12 (m, 1H), 5.91 (q, J = 6.8 Hz, 1H), 3.90-3.85 (m, 4H), 3.60 (s, 2H), 3.48-3.42 (m, 4H), 2.17 (s, 6H), 1.82 (d, J = 6.8 Hz, 3H ). Example 2-2 N -(( R )-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-7-((( S )-pyrrolidin-3-yl)oxy Base) eh

-1-amine

-1-胺（80.0 mg，195 µmol，1.00當量）於甲苯（2.00 mL）中之溶液中添加氫化鈉（15.6 mg，390 µmol，60.0%純度，2.00當量）。隨後將(S )-3-羥基吡咯啶-1-羧酸第三丁酯（110 mg，585 µmol，3.00當量）、Pd₂ (dba)₃ （17.9 mg，19.5 µmol，0.10當量）及Tol-BINAP（132 mg，195 µmol，1.00當量）添加至反應混合物中，且將混合物加熱至100℃持續1小時。將反應混合物冷卻至25℃，倒入水（20.0 mL）中，且用乙酸乙酯（20.0 mL×3）萃取。將合併之有機相在真空下濃縮，得到殘餘物。將殘餘物藉由逆相HPLC[水（0.1% TFA）-ACN]純化，得到呈黃色固體狀之(S )-3-((4-(((R )-1-(2-甲基-3-(三氟甲基)苯基)乙基)胺基)呔

-6-基)氧基)吡咯啶-1-羧酸第三丁酯（35.0 mg，44.0 µmol，23.0%產率，65.0%純度）。LCMS [M+1]: 517.0。 Step A: Add (R )-7-bromo- N -(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl) to (R )-7-bromo-N -(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl) under a nitrogen atmosphere at 0°C

To a solution of -1-amine (80.0 mg, 195 µmol, 1.00 equivalent) in toluene (2.00 mL) was added sodium hydride (15.6 mg, 390 µmol, 60.0% purity, 2.00 equivalent). Then ( S )-3-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester (110 mg, 585 µmol, 3.00 equivalents), Pd ₂ (dba) ₃ (17.9 mg, 19.5 µmol, 0.10 equivalents) and Tol- BINAP (132 mg, 195 µmol, 1.00 equivalent) was added to the reaction mixture, and the mixture was heated to 100°C for 1 hour. The reaction mixture was cooled to 25°C, poured into water (20.0 mL), and extracted with ethyl acetate (20.0 mL×3). The combined organic phase was concentrated under vacuum to obtain a residue. The residue was purified by reverse phase HPLC [water (0.1% TFA)-ACN] to obtain ( S )-3-((4-((( R )-1-(2-methyl- 3-(trifluoromethyl)phenyl)ethyl)amino)

-6-yl)oxy)pyrrolidine-1-carboxylic acid tert-butyl ester (35.0 mg, 44.0 µmol, 23.0% yield, 65.0% purity). LCMS [M+1]: 517.0.

-6-基)氧基)吡咯啶-1-羧酸第三丁酯（35.0 mg，44.0 µmol，1.00當量）於乙腈（1.00 mL）中之溶液中逐滴添加HCl（4.00 M於二

烷中，11.0 µL，1.00當量）。將反應混合物在0℃下攪拌30分鐘，隨後在真空下濃縮，得到殘餘物。將殘餘物藉由逆相製備型HPLC（管柱：Phenomenex Gemini-NX C18 75×30 mm×3 um；移動相：[水（0.1% TFA）-乙腈]；B%：25%-35%）純化，得到呈黃色固體狀之N -((R )-1-(2-甲基-3-(三氟甲基)苯基)乙基)-7-(((S )-吡咯啶-3-基)氧基)呔

-1-胺（8.01 mg，18.2 µmol，41.0%產率，95%純度）。LCMS [M+1]: 417.1。Step B: In a nitrogen atmosphere at 0°C, add ( S )-3-((4-((( R )-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl) )Amino)

-6-yl)oxy)pyrrolidine-1-carboxylic acid tert-butyl ester (35.0 mg, 44.0 µmol, 1.00 equivalent) in acetonitrile (1.00 mL) was added dropwise HCl (4.00 M in two

In alkane, 11.0 µL, 1.00 equivalent). The reaction mixture was stirred at 0°C for 30 minutes and then concentrated under vacuum to obtain a residue. The residue was subjected to reverse phase preparative HPLC (column: Phenomenex Gemini-NX C18 75×30 mm×3 um; mobile phase: [water (0.1% TFA)-acetonitrile]; B%: 25%-35%) Purified to obtain N -(( R )-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-7-((( S )-pyrrolidine-3 as a yellow solid -Radical) oxy) 呔

-1-amine (8.01 mg, 18.2 µmol, 41.0% yield, 95% purity). LCMS [M+1]: 417.1.

¹ H NMR (400 MHz, CD ₃ OD) δ = 9.15 (s, 1H), 8.28-8.21 (m, 2H), 7.80-7.72 (m, 2H), 7.59 (d, J = 7.6 Hz, 1H), 7.37-7.27 (t, J = 7.6 Hz, 1H), 5.67-5.57 (m, 2H), 3.80-3.67 (m, 2H), 3.64-3.47 (m, 2H), 2.63 (s, 3H), 2.55- 2.46 (m, 2H), 1.73 (d, J = 6.8 Hz, 3H).

(R )-N -(1-(2-甲基-3-(三氟甲基)苯基)乙基)-7-(哌啶-4-基氧基)呔

-1-胺 ¹ H NMR (400 MHz, CD₃ OD) δ 9.14 (s, 1H), 8.28 - 2.11 (m, 2H), 7.83 (dd,J = 2.0, 8.8 Hz, 1H), 7.76 (br d,J = 8.0 Hz, 1H), 7.59 (br d,J = 7.6 Hz, 1H), 7.33 (t,J = 7.6 Hz, 1H), 5.62 (q,J = 6.8 Hz, 1H), 5.19 -5.18 (m, 2H), 3.55 - 3.44 (m, 2H), 3.36 - 3.35 (m, 2H), 2.64 (s, 3H), 2.34 - 2.32 (m, 2H), 2.26 - 2.11 (m, 2H), 1.73 (d,J = 6.8 Hz, 3H)。LCMS [M+1]: 431.3。 2-4

N -((R )-1-(2-甲基-3-(三氟甲基)苯基)乙基)-7-(((S )-四氫呋喃-3-基)氧基)呔

-1-胺 ¹ H NMR (400 MHz, CDCl₃ ) δ 8.92 (s, 1H), 8.58 (s, 1H), 8.09 (s, 1H), 7.75 (d,J = 8.8 Hz, 1H), 7.64 d,J = 8.0 Hz, 1H), 7.53 - 7.50 (m, 2H), 7.21 (t,J = 7.6 Hz, 1H), 5.43 - 5.40 (m, 1H), 5.33 (s, 1H), 4.11 - 4.04 (m, 3H), 3.96 - 3.93 (m, 1H), 2.52 (s, 3H), 2.50 - 2.44 (m, 1H), 2.16 - 2.11(m, 1H), 1.69 - 1.67 (d,J = 7.2 Hz, 3H)。LCMS [M+1]: 418.2。 2-5

N -((R )-1-(2-甲基-3-(三氟甲基)苯基)乙基)-7-((1,2,2-三甲基吡咯啶-3-基)氧基)呔

-1-胺 LCMS [M+1]: 459.1。 2-6

(R )-N -(1-(2-甲基-3-(三氟甲基)苯基)乙基)-7-((1-甲基哌啶-4-基)氧基)呔

-1-胺 LCMS [M+1]: 445.2。 2-7

N -((R )-1-(2-甲基-3-(三氟甲基)苯基)乙基)-7-((1-甲基吡咯啶-3-基)氧基)呔

-1-胺 LCMS [M+1]: 431.2。 2-8

7-((反式 )-3-(二甲基胺基)環丁氧基)-N -((R )-1-(2-甲基-3-(三氟甲基)苯基)乙基)呔

-1-胺 LCMS [M+1]: 445.2。 2-9

(R )-7-((1-(2-甲氧基乙基)哌啶-4-基)氧基)-N -(1-(2-甲基-3-(三氟甲基)苯基)乙基)呔

-1-胺 LCMS [M+1]: 489.2。 2-10

N -((R )-1-(2-甲基-3-(三氟甲基)苯基)乙基)-7-((8-甲基-8-氮雜雙環[3.2.1]辛-3-基)氧基)呔

-1-胺 LCMS [M+1]: 472.2。 2-11

7-(((反式 )-3-(二甲基胺基)環戊基)氧基)-N -((R )-1-(2-甲基-3-(三氟甲基)苯基)乙基)呔

-1-胺 LCMS [M+1]: 459.1。 2-12

N -((R )-1-(2-甲基-3-(三氟甲基)苯基)乙基)-7-((八氫吲口巾-7-基)氧基)呔

-1-胺 LCMS [M+1]: 471.1。 實例3-1 (R )-N -(1-(2-甲基-3-(三氟甲基)苯基)乙基)-7-(哌

-1-基)吡啶并[3,4-d ]嗒

-1-胺

Following the teaching of General Reaction Scheme III and the procedure of Preparation Example 2-2, the following compounds of formula (I) as shown in Table 2 were prepared, Examples 2-3 to 2-12: Table 2 Example # structure Spectral data 2-3

( R ) -N -(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-7-(piperidin-4-yloxy)

-1-amine ¹ H NMR (400 MHz, CD ₃ OD) δ 9.14 (s, 1H), 8.28-2.11 (m, 2H), 7.83 (dd, J = 2.0, 8.8 Hz, 1H), 7.76 (br d, J = 8.0 Hz, 1H), 7.59 (br d, J = 7.6 Hz, 1H), 7.33 (t, J = 7.6 Hz, 1H), 5.62 (q, J = 6.8 Hz, 1H), 5.19 -5.18 (m, 2H) , 3.55-3.44 (m, 2H), 3.36-3.35 (m, 2H), 2.64 (s, 3H), 2.34-2.32 (m, 2H), 2.26-2.11 (m, 2H), 1.73 (d, J = 6.8 Hz, 3H). LCMS [M+1]: 431.3. 2-4

N -(( R )-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-7-((( S )-tetrahydrofuran-3-yl)oxy)

-1-amine ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.92 (s, 1H), 8.58 (s, 1H), 8.09 (s, 1H), 7.75 (d, J = 8.8 Hz, 1H), 7.64 d, J = 8.0 Hz, 1H), 7.53-7.50 (m, 2H), 7.21 (t, J = 7.6 Hz, 1H), 5.43-5.40 (m, 1H), 5.33 (s, 1H), 4.11-4.04 (m, 3H) , 3.96-3.93 (m, 1H), 2.52 (s, 3H), 2.50-2.44 (m, 1H), 2.16-2.11(m, 1H), 1.69-1.67 (d, J = 7.2 Hz, 3H). LCMS [M+1]: 418.2. 2-5

N -(( R )-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-7-((1,2,2-trimethylpyrrolidin-3-yl) Oxy)

-1-amine LCMS [M+1]: 459.1. 2-6

( R ) -N -(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-7-((1-methylpiperidin-4-yl)oxy)

-1-amine LCMS [M+1]: 445.2. 2-7

N -(( R )-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-7-((1-methylpyrrolidin-3-yl)oxy)

-1-amine LCMS [M+1]: 431.2. 2-8

7-(( trans )-3-(dimethylamino)cyclobutoxy) -N -(( R )-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl Base) eh

-1-amine LCMS [M+1]: 445.2. 2-9

( R )-7-((1-(2-methoxyethyl)piperidin-4-yl)oxy) -N -(1-(2-methyl-3-(trifluoromethyl)benzene (Base) ethyl) 呔

-1-amine LCMS [M+1]: 489.2. 2-10

N -(( R )-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-7-((8-methyl-8-azabicyclo[3.2.1]octane -3-yl)oxy)

-1-amine LCMS [M+1]: 472.2. 2-11

7-((( trans )-3-(dimethylamino)cyclopentyl)oxy) -N -(( R )-1-(2-methyl-3-(trifluoromethyl)benzene (Base) ethyl) 呔

-1-amine LCMS [M+1]: 459.1. 2-12

N -(( R )-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-7-((octahydroindole-7-yl)oxy)

-1-amine LCMS [M+1]: 471.1. Example 3-1 ( R ) -N -(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-7-(piper

-1-yl)pyrido[3,4- d ]

-1-amine

（40.0 mg，200 µmol，1.00當量）及(R )-1-(2-甲基-3-(三氟甲基)苯基)乙-1-胺（40.6 mg，200 µmol，1.00當量）於DMSO（1.00 mL）中之溶液中添加二異丙基乙胺（77.5 mg，600 µmol，105 µL，3.00當量）及氟化鉀（34.8 mg，600 µmol，14.05 µL，3.00當量）。將反應混合物在氮氣氛圍下在130℃下攪拌1小時，隨後冷卻至25℃，倒入水（3.00 mL）中且攪拌5分鐘。用乙酸乙酯（5.00 mL×3）萃取水相，且將合併之有機相用鹽水（3.00 mL×2）洗滌，經無水硫酸鈉乾燥，過濾，且真空濃縮，得到殘餘物。將殘餘物藉由製備型TLC（SiO₂ ，石油醚/乙酸乙酯＝1/1）純化，得到呈黃色固體狀之(R )-7-氯-N -(1-(2-甲基-3-(三氟甲基)苯基)乙基)吡啶并[3,4-d ]嗒

-1-胺（30.0 mg，81.8 µmol，40.9%產率）。LCMS [M+1]: 367.2。Step A: Under nitrogen atmosphere, to 1,7-dichloropyrido[3,4- d ]

(40.0 mg, 200 µmol, 1.00 equivalent) and ( R )-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl-1-amine (40.6 mg, 200 µmol, 1.00 equivalent) in Add diisopropylethylamine (77.5 mg, 600 µmol, 105 µL, 3.00 equivalents) and potassium fluoride (34.8 mg, 600 µmol, 14.05 µL, 3.00 equivalents) to the solution in DMSO (1.00 mL). The reaction mixture was stirred at 130°C for 1 hour under a nitrogen atmosphere, then cooled to 25°C, poured into water (3.00 mL) and stirred for 5 minutes. The aqueous phase was extracted with ethyl acetate (5.00 mL×3), and the combined organic phase was washed with brine (3.00 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to obtain a residue. The residue was purified by preparative TLC (SiO ₂ , petroleum ether/ethyl acetate = 1/1) to obtain ( R )-7-chloro- N -(1-(2-methyl-) as a yellow solid 3-(Trifluoromethyl)phenyl)ethyl)pyrido[3,4- d ]

-1-amine (30.0 mg, 81.8 µmol, 40.9% yield). LCMS [M+1]: 367.2.

¹ H NMR (400 MHz, CD ₃ OD) δ = 9.14 (s, 1H), 8.95 (s, 1H), 8.49 (s, 1H), 7.69 (d, J = 7.6 Hz, 1H), 7.51 (d, J = 7.6 Hz, 1H), 7.26 (t, J = 8.0 Hz, 1H), 5.76 (q, J = 6.8 Hz, 1H), 2.63 (s, 3H), 1.64 (d, J = 6.8 Hz, 3H) .

-1-胺（18.0 mg，49.1 µmol，1.00當量）及哌

-1-羧酸第三丁酯（13.7 mg，73.6 µmol，1.50當量）於二

烷（0.50 mL）中之溶液中添加第三丁醇鉀（1.00 M，98.2 µL，2.00當量）及RuPhos-Pd-G3（4.10 mg，4.91 µmol，0.10當量）。將反應混合物在100℃下攪拌1小時，隨後冷卻至25℃，且在真空下濃縮，得到殘餘物。將殘餘物藉由製備型TLC（SiO₂ ，石油醚/乙酸乙酯＝1/1）純化，得到呈黃色固體狀之(R )-4-(1-((1-(2-甲基-3-(三氟甲基)苯基)乙基)胺基)吡啶并[3,4-d ]嗒

-7-基)哌

-1-羧酸第三丁酯（18.0 mg，粗製）。LCMS [M+1]: 517.3。Step B: Under nitrogen atmosphere, to ( R )-7-chloro- N -(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)pyrido[3,4- d ]despair

-1-amine (18.0 mg, 49.1 µmol, 1.00 equivalent) and piper

-1- tert-butyl carboxylate (13.7 mg, 73.6 µmol, 1.50 equivalent) in two

Add potassium tert-butoxide (1.00 M, 98.2 µL, 2.00 equivalent) and RuPhos-Pd-G3 (4.10 mg, 4.91 µmol, 0.10 equivalent) to the solution in alkane (0.50 mL). The reaction mixture was stirred at 100°C for 1 hour, then cooled to 25°C, and concentrated under vacuum to give a residue. The residue was purified by preparative TLC (SiO ₂ , petroleum ether/ethyl acetate = 1/1) to obtain ( R )-4-(1-((1-(2-methyl- 3-(Trifluoromethyl)phenyl)ethyl)amino)pyrido[3,4- d ]

-7-yl)piperidine

-1- tert-butyl carboxylate (18.0 mg, crude). LCMS [M+1]: 517.3.

-7-基)哌

-1-羧酸第三丁酯（11.0 mg，21.3 µmol，1.00當量）於乙腈（1.00 mL）中之溶液中添加含HCl之二

烷（3 M，0.50 mL）。將反應混合物在0℃下攪拌1小時，隨後真空濃縮，得到殘餘物。將殘餘物藉由製備型HPLC（管柱：Phenomenex luna C18 150×25 mm×10 um；移動相：[水（0.1% TFA）-ACN]；B%：10%-40%）純化，得到呈白色固體狀之(R)-N-(1-(2-甲基-3-(三氟甲基)苯基)乙基)-7-(哌

-1-基)吡啶并[3,4-d]嗒

-1-胺（4.50 mg，8.48 µmol，39.8%產率，三氟乙酸鹽）。LCMS [M+1] = 417.1。Step C: To (R)-4-(1-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyrido[3,4-d]

-7-yl)piperidine

-1- tert-butyl carboxylate (11.0 mg, 21.3 µmol, 1.00 equivalent) in acetonitrile (1.00 mL) was added with HCl bis

Alkane (3 M, 0.50 mL). The reaction mixture was stirred at 0°C for 1 hour and then concentrated in vacuo to obtain a residue. The residue was purified by preparative HPLC (column: Phenomenex luna C18 150×25 mm×10 um; mobile phase: [water (0.1% TFA)-ACN]; B%: 10%-40%) to obtain (R)-N-(1-(2-Methyl-3-(trifluoromethyl)phenyl)ethyl)-7-(piper

-1-yl)pyrido[3,4-d]ta

-1-amine (4.50 mg, 8.48 µmol, 39.8% yield, trifluoroacetate salt). LCMS [M+1] = 417.1.

1H NMR (400 MHz, CD3OD) δ = 9.18 (s, 1H), 9.05 (s, 1H), 7.76 (s, 1H), 7.71 (d, J =8.0 Hz, 1H), 7.56 (d, J = 7.2 Hz, 1H), 7.36-7.27 (m, 1H), 5.58 (q, J = 6.8 Hz, 1H), 4.30-4.21 (m, 4H), 3.50-3.38 (m, 4H), 2.61 (s, 3H) , 1.69 (d, J = 6.8 Hz, 3H).

SFC: Chiralpak OJ-3 (50×4.6 mm inner diameter, 3 um); mobile phase: phase A is CO2, phase B is MeOH (0.05% DEA); gradient dissolution: 50% MeOH (0.05% DEA) in 5% To 40% CO2. Flow rate: 3 ml/min; detector: PDA; column temperature: 35°C; back pressure: 100 Bar.

(R )-N -(1-(4-(2-((甲基胺基)甲基)苯基)噻吩-2-基)乙基)-7-

啉基吡啶并[3,4-d ]嗒

-1-胺 ¹ H NMR (400M Hz, CD₃ OD) δ  8.93 (d,J = 0.8 Hz, 1H), 8.70 (s, 1H), 7.44 (d,J = 6.4 Hz, 1H), 7.37 - 7.29 (m, 4H), 7.22 - 7.15 (m, 2H), 5.91 (q,J = 6.8 Hz, 1H), 3.87 - 3.82 (m, 4H), 3.80 - 3.74 (m, 6H), 2.27 (s, 3H), 1.83 (d,J = 7.2 Hz, 3H)。LCMS [M+1]: 461.3。 3-3

(R )-N -(1-(5-(2-((甲基胺基)甲基)苯基)噻吩-2-基)乙基)-7-

啉基吡啶并[3,4-d ]嗒

-1-胺 ¹ H NMR (400 MHz, CD₃ OD) δ = 9.14 (s, 1H), 9.04 (s, 1H), 7.60 - 7.55 (m, 1H), 7.53 - 7.49 (m, 2H), 7.48 - 7.44 (m, 2H), 7.20 (d,J = 4.0 Hz, 1H), 7.01 (d,J = 4.0 Hz, 1H), 5.73 (q,J = 6.8 Hz, 1H), 4.34 (s, 2H), 4.01 - 3.89 (m, 4H), 3.88 - 3.77 (m, 4H), 2.64 (s, 3H), 1.85 (d,J = 7.2 Hz, 3H)。LCMS [M+1]: 461.2。 3-4

(R )-7-甲氧基-N -(1-(4-(2-((甲基胺基)甲基)苯基)噻吩-2-基)乙基)吡啶并[3,4-d ]嗒

-1-胺 ¹ H NMR (400 MHz, CD₃ OD) δ 9.32 - 9.30 (m, 1H), 9.25 - 9.22 (m, 1H), 7.91 - 7.89 (m, 1H), 7.59 - 7.55 (m, 1H), 7.51 - 7.45 (m, 2H), 7.45 - 7.39 (m, 1H), 7.37 - 7.34 (m, 1H), 7.27 - 7.25 (m, 1H), 5.80 - 5.73 (m, 1H), 4.28 (s, 2H), 4.19 (s, 3H), 2.60 (s, 3H), 1.88 (d,J = 6.9 Hz, 3H)。LCMS [M+1]: 406.1。 3-5

(R )-4-(1-((1-(4-(2-((甲基胺基)甲基)苯基)噻吩-2-基)乙基)胺基)吡啶并[3,4-d ]嗒

-7-基)哌

-2-酮 ¹ H NMR (400 MHz, CD₃ OD) δ 9.20 (s, 1H), 9.09 (s, 1H), 7.59 - 7.55 (m, 1H), 7.53 - 7.46 (m, 3H), 7.45 - 7.39 (m, 1H), 7.33 (d,J = 1.5 Hz, 1H), 7.25 - 7.23 (m, 1H), 5.77 (q,J = 6.8 Hz, 1H), 4.42 (s, 2H), 4.29 (s, 2H), 4.23 - 4.16 (m, 2H), 3.54 (t,J = 5.4 Hz, 2H), 2.61 (s, 3H), 1.88 (d,J = 6.9 Hz, 3H).LCMS [M+1]: 474.2。 3-6

(R)-1-(1-((1-(4-(2-((甲基胺基)甲基)苯基)噻吩-2-基)乙基)胺基)吡啶并[3,4-d]嗒

-7-基)哌

-2-酮 ¹ H NMR (400 MHz, CD₃ OD) δ 9.43 (d,J = 0.9 Hz, 1H), 9.19 (d,J = 0.9 Hz, 1H), 9.07 - 9.05 (m, 1H), 7.57 - 7.51 (m, 1H), 7.48 - 7.42 (m, 2H), 7.41 - 7.36 (m, 1H), 7.34 (d,J = 1.5 Hz, 1H), 7.27 - 7.25 (m, 1H), 5.80 - 5.74 (m, 1H), 4.47 - 4.41 (m, 2H), 4.25 (s, 2H), 4.17 (s, 2H), 3.76 - 3.72 (m, 2H), 2.58 (s, 3H), 1.89 (d,J = 6.8 Hz, 3H)。LCMS [M+1]: 474.4。 實例4-1 (R )-6,7-二甲氧基-4-甲基-N -(1-(2-甲基-3-(三氟甲基)苯基)乙基)呔

-1-胺

Following the teaching of General Reaction Scheme III and the preparation of Preparation Example 3-1, the following compounds of formula (I) as shown in Table 3 were prepared, Example 3-2-3-6: Table 3 Example # structure Spectral data 3-2

( R ) -N -(1-(4-(2-((methylamino)methyl)phenyl)thiophen-2-yl)ethyl)-7-

Hydroxypyrido[3,4- d ]

-1-amine ¹ H NMR (400M Hz, CD ₃ OD) δ 8.93 (d, J = 0.8 Hz, 1H), 8.70 (s, 1H), 7.44 (d, J = 6.4 Hz, 1H), 7.37-7.29 (m, 4H ), 7.22-7.15 (m, 2H), 5.91 (q, J = 6.8 Hz, 1H), 3.87-3.82 (m, 4H), 3.80-3.74 (m, 6H), 2.27 (s, 3H), 1.83 ( d, J = 7.2 Hz, 3H). LCMS [M+1]: 461.3. 3-3

( R ) -N -(1-(5-(2-((Methylamino)methyl)phenyl)thiophen-2-yl)ethyl)-7-

Hydroxypyrido[3,4- d ]

-1-amine ¹ H NMR (400 MHz, CD ₃ OD) δ = 9.14 (s, 1H), 9.04 (s, 1H), 7.60-7.55 (m, 1H), 7.53-7.49 (m, 2H), 7.48-7.44 (m , 2H), 7.20 (d, J = 4.0 Hz, 1H), 7.01 (d, J = 4.0 Hz, 1H), 5.73 (q, J = 6.8 Hz, 1H), 4.34 (s, 2H), 4.01-3.89 (m, 4H), 3.88-3.77 (m, 4H), 2.64 (s, 3H), 1.85 (d, J = 7.2 Hz, 3H). LCMS [M+1]: 461.2. 3-4

( R )-7-Methoxy- N -(1-(4-(2-((methylamino)methyl)phenyl)thiophen-2-yl)ethyl)pyrido[3,4- d ]

-1-amine ¹ H NMR (400 MHz, CD ₃ OD) δ 9.32-9.30 (m, 1H), 9.25-9.22 (m, 1H), 7.91-7.89 (m, 1H), 7.59-7.55 (m, 1H), 7.51- 7.45 (m, 2H), 7.45-7.39 (m, 1H), 7.37-7.34 (m, 1H), 7.27-7.25 (m, 1H), 5.80-5.73 (m, 1H), 4.28 (s, 2H), 4.19 (s, 3H), 2.60 (s, 3H), 1.88 (d, J = 6.9 Hz, 3H). LCMS [M+1]: 406.1. 3-5

( R )-4-(1-((1-(4-(2-((methylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino)pyrido(3,4 -d ] Da

-7-yl)piperidine

-2-one ¹ H NMR (400 MHz, CD ₃ OD) δ 9.20 (s, 1H), 9.09 (s, 1H), 7.59-7.55 (m, 1H), 7.53-7.46 (m, 3H), 7.45-7.39 (m, 1H), 7.33 (d, J = 1.5 Hz, 1H), 7.25-7.23 (m, 1H), 5.77 (q, J = 6.8 Hz, 1H), 4.42 (s, 2H), 4.29 (s, 2H), 4.23-4.16 (m, 2H), 3.54 (t, J = 5.4 Hz, 2H), 2.61 (s, 3H), 1.88 (d, J = 6.9 Hz, 3H). LCMS [M+1]: 474.2. 3-6

(R)-1-(1-((1-(4-(2-((Methylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino)pyrido[3,4 -d] Da

-7-yl)piperidine

-2-one ¹ H NMR (400 MHz, CD ₃ OD) δ 9.43 (d, J = 0.9 Hz, 1H), 9.19 (d, J = 0.9 Hz, 1H), 9.07-9.05 (m, 1H), 7.57-7.51 (m , 1H), 7.48-7.42 (m, 2H), 7.41-7.36 (m, 1H), 7.34 (d, J = 1.5 Hz, 1H), 7.27-7.25 (m, 1H), 5.80-5.74 (m, 1H) ), 4.47-4.41 (m, 2H), 4.25 (s, 2H), 4.17 (s, 2H), 3.76-3.72 (m, 2H), 2.58 (s, 3H), 1.89 (d, J = 6.8 Hz, 3H). LCMS [M+1]: 474.4. Example 4-1 ( R )-6,7-Dimethoxy-4-methyl- N -(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)

-1-amine

（100 mg，419 µmol，1.00當量）、(R )-1-(2-甲基-3-(三氟甲基)苯基)乙-1-胺（85.1 mg，419 µmol，1.00當量）、BrettPhos Pd G3（38.0 mg，41.9 µmol，0.10當量）及第三丁醇鉀（1.00 M，1.26 mL，3.00當量）於甲苯（2.00 mL）中之混合物脫氣且用氮氣沖洗3次。將反應混合物在氮氣氛圍下在100℃下攪拌1小時，隨後冷卻至25℃，過濾，且將濾液在減壓下濃縮，得到殘餘物。將殘餘物藉由製備型HPLC（管柱：Waters Xbridge BEH C18 100×25 mm×5 um；移動相：[水（10mM NH₄ HCO₃ ）-ACN]；B%：35%-65%）純化，得到呈白色固體狀之(R )-6,7-二甲氧基-4-甲基-N -(1-(2-甲基-3-(三氟甲基)苯基)乙基)呔

-1-胺（8.24 mg，20.3 µmol，4.84%產率，99.8%純度）。LCMS [M+1]: 406.2。Add 1-chloro-6,7-dimethoxy-4-methyl

(100 mg, 419 µmol, 1.00 equivalent), ( R )-1-(2-methyl-3-(trifluoromethyl)phenyl)ethan-1-amine (85.1 mg, 419 µmol, 1.00 equivalent), The mixture of BrettPhos Pd G3 (38.0 mg, 41.9 µmol, 0.10 equivalent) and potassium tert-butoxide (1.00 M, 1.26 mL, 3.00 equivalent) in toluene (2.00 mL) was degassed and flushed with nitrogen 3 times. The reaction mixture was stirred at 100°C for 1 hour under a nitrogen atmosphere, then cooled to 25°C, filtered, and the filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by preparative HPLC (column: Waters Xbridge BEH C18 100×25 mm×5 um; mobile phase: [water (10mM NH ₄ HCO ₃ )-ACN]; B%: 35%-65%) To obtain (R )-6,7-dimethoxy-4-methyl- N -(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl) as a white solid Hum

-1-amine (8.24 mg, 20.3 µmol, 4.84% yield, 99.8% purity). LCMS [M+1]: 406.2.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 7.83 (s, 1H), 7.76 (d, J = 7.6 Hz, 1H), 7.51 (d, J = 8.0 Hz, 1H), 7.39 (d, J = 6.8 Hz, 1H), 7.33-7.27 (m, 1H), 7.22 (s, 1H), 5.73-5.64 (m, 1H), 4.01 (s, 3H), 3.95 (s, 3H), 2.58 (s, 6H), 1.55 (d, J = 7.2 Hz, 3H).

N -(1-(5-(2-((二甲基胺基)甲基)苯基)噻吩-2-基)乙基)-6,7-二甲氧基-4-甲基呔

-1-胺 ¹ H NMR (400 MHz, DMSO-d₆ ) δ  7.74 (s, 1H), 7.44 - 7.40 (m, 1H), 7.40 - 7.33 (m, 2H), 7.31 - 7.27 (m, 2H), 7.26 (s, 1H), 7.16 (d,J = 4.0 Hz, 1H), 7.06 (d,J = 3.6 Hz, 1H), 5.96 - 5.87 (m, 1H), 3.96 (s, 3H), 3.95 (s, 3H), 3.37 (s, 2 H), 2.66 (s, 3H), 2.10 (s, 6H), 1.72 (d,J = 6.8 Hz, 3H)。 LCMS [M+1]⁺ : 463.2。 4-3

6,7-二甲氧基-4-甲基-N -(1-(5-(2-((甲基胺基)甲基)苯基)噻吩-2-基)乙基)呔

-1-胺 ¹ H NMR (400 MHz, CDCl₃ ) δ 7.44 (d,J = 7.2 Hz, 1H), 7.39 (dd,J = 0.8, 7.2 Hz, 1H), 7.33 - 7.29 (m, 2H), 7.17 (s, 1H), 7.11 (d,J = 3.2 Hz, 1H), 7.01 (d,J = 3.6 Hz, 1H), 6.98 (s, 1H), 6.06-6.02 (m, 1H), 4.98 - 4.96 (m, 1H), 4.06 (s, 6H), 3.85 (s, 2H), 2.80 (s, 3H), 2.41 (s, 3H), 1.83 (d,J = 6.8 Hz, 3H)。LCMS [M+1]: 449.2。 4-4

(R )-6,7-二甲氧基-4-甲基-N -(1-(4-(2-((甲基胺基)甲基)苯基)噻吩-2-基)乙基)呔

-1-胺 ¹ H NMR (400 MHz, DMSO-d₆ ) δ = 7.74 (s, 1H), 7.47 - 7.42 (m, 1H), 7.42 (d,J = 1.6 Hz, 1H), 7.34 (d,J = 8.4 Hz, 1H), 7.32 - 7.24 (m, 5H), 5.97 - 5.87 (m, 1H), 3.97 (s, 3H), 3.96 (s, 3H) 3.57 (s, 2H), 2.66 (s, 3H), 2.22 (s, 3H), 1.73 (d,J = 6.8 Hz, 3H)。LCMS [M+1]: 449.2。 實例5-1 (R )-N -(1-(5-(2-((二甲基胺基)甲基)苯基)噻吩-2-基)乙基)-4-異丙基-6,7-二甲氧基呔

-1-胺

Following the teaching of General Reaction Scheme IV and the procedure of Preparation Example 4-1, the following compounds of formula (I) as shown in Table 4 were prepared, Example 4-2-4-4: Table 4 Example # structure Spectral data 4-2

N -(1-(5-(2-((dimethylamino)methyl)phenyl)thiophen-2-yl)ethyl)-6,7-dimethoxy-4-methyl

-1-amine ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.74 (s, 1H), 7.44-7.40 (m, 1H), 7.40-7.33 (m, 2H), 7.31-7.27 (m, 2H), 7.26 (s , 1H), 7.16 (d, J = 4.0 Hz, 1H), 7.06 (d, J = 3.6 Hz, 1H), 5.96-5.87 (m, 1H), 3.96 (s, 3H), 3.95 (s, 3H) , 3.37 (s, 2 H), 2.66 (s, 3H), 2.10 (s, 6H), 1.72 (d, J = 6.8 Hz, 3H). LCMS [M+1] ⁺ : 463.2. 4-3

6,7-Dimethoxy-4-methyl- N -(1-(5-(2-((methylamino)methyl)phenyl)thiophen-2-yl)ethyl)

-1-amine ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.44 (d, J = 7.2 Hz, 1H), 7.39 (dd, J = 0.8, 7.2 Hz, 1H), 7.33-7.29 (m, 2H), 7.17 (s, 1H), 7.11 (d, J = 3.2 Hz, 1H), 7.01 (d, J = 3.6 Hz, 1H), 6.98 (s, 1H), 6.06-6.02 (m, 1H), 4.98-4.96 (m, 1H ), 4.06 (s, 6H), 3.85 (s, 2H), 2.80 (s, 3H), 2.41 (s, 3H), 1.83 (d, J = 6.8 Hz, 3H). LCMS [M+1]: 449.2. 4-4

( R )-6,7-Dimethoxy-4-methyl- N -(1-(4-(2-((methylamino)methyl)phenyl)thiophen-2-yl)ethyl ) Eh

-1-amine ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 7.74 (s, 1H), 7.47-7.42 (m, 1H), 7.42 (d, J = 1.6 Hz, 1H), 7.34 (d, J = 8.4 Hz , 1H), 7.32-7.24 (m, 5H), 5.97-5.87 (m, 1H), 3.97 (s, 3H), 3.96 (s, 3H) 3.57 (s, 2H), 2.66 (s, 3H), 2.22 (s, 3H), 1.73 (d, J = 6.8 Hz, 3H). LCMS [M+1]: 449.2. Example 5-1 ( R ) -N -(1-(5-(2-((Dimethylamino)methyl)phenyl)thiophen-2-yl)ethyl)-4-isopropyl-6 ,7-Dimethoxy

-1-amine

（221 mg，853 µmol，1.00當量）、N ,N -二異丙基乙胺（331 mg，2.56 mmol，446 µL，3.00當量）及氟化鉀（149 mg，2.56 mmol，60.0 µL，3.00當量）於DMSO（3.00 mL）中之混合物在130℃下攪拌12小時。隨後將反應混合物冷卻至25℃，隨後添加乙酸乙酯（5.00 mL）及水（8.00 mL），且分離各層。用乙酸乙酯（10.0 mL×2）萃取水相，且將合併之有機層用鹽水（10.0 mL×2）洗滌，經硫酸鈉乾燥，過濾，且在減壓下濃縮，得到殘餘物。將殘餘物藉由製備型TLC（SiO₂ ，石油醚/乙酸乙酯=1/1）純化， 得到呈黃色固體狀之(R )-4-氯-N-(1-(5-(2-((二甲基胺基)甲基)苯基)噻吩-2-基)乙基)-6,7-二甲氧基呔

-1-胺（100 mg，24.3%產率）。LCMS [M+1]: 483.0。Step A: Add ( R )-1-(5-(2-((dimethylamino)methyl)phenyl)thiophen-2-yl)ethan-1-amine (200 mg, 768 µmol, 0.90 equivalent) ), 1,4-Dichloro-6,7-Dimethoxy-E

(221 mg, 853 µmol, 1.00 equivalent), N , N -diisopropylethylamine (331 mg, 2.56 mmol, 446 µL, 3.00 equivalent) and potassium fluoride (149 mg, 2.56 mmol, 60.0 µL, 3.00 equivalent) ) The mixture in DMSO (3.00 mL) was stirred at 130°C for 12 hours. The reaction mixture was then cooled to 25°C, then ethyl acetate (5.00 mL) and water (8.00 mL) were added, and the layers were separated. The aqueous phase was extracted with ethyl acetate (10.0 mL×2), and the combined organic layer was washed with brine (10.0 mL×2), dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified (SiO _2, petroleum ether / ethyl acetate = 1/1) was purified by preparative TLC, to give a yellow solid of (R) -4- chloro -N- (1- (5- (2- ((Dimethylamino)methyl)phenyl)thiophen-2-yl)ethyl)-6,7-dimethoxy

-1-amine (100 mg, 24.3% yield). LCMS [M+1]: 483.0.

¹ H NMR (400 MHz, CDCl ₃ ) δ = 7.53-7.49 (m, 1H), 7.44 (s, 1H), 7.44-7.40 (m, 1H), 7.34-7.29 (m, 2H), 7.13-7.05 ( m, 2H), 6.99 (s, 1H), 6.06-5.96 (m, 1H), 4.09 (s, 3H), 4.07 (s, 3H), 3.60 (s, 2H), 2.27 (s, 6H), 1.84 (d, J = 6.4 Hz, 3H).

-1-胺（40.0 mg，82.8 µmol，1.00當量）及乙醯丙酮鐵（III）（80.0 mg，226 µmol，2.74當量）於THF（1.00 mL）及1-甲基-2-吡咯啶酮（0.01 mL）中之溶液中逐滴添加異丙基氯化鎂（3.00 M於THF中，600 µL，21.7當量）。添加後，將混合物反應在25℃下攪拌10分鐘。將反應混合物藉由添加飽和氯化銨溶液（5.00 mL）來淬滅，且用乙酸乙酯（1.00 mL×3）萃取。將合併之有機層用鹽水（2.00 mL×2）洗滌，經硫酸鈉乾燥，過濾且在減壓下濃縮，得到殘餘物。將殘餘物藉由製備型HPLC（管柱：Phenomenex luna C18 150×25 mm×10 um；移動相：[水（0.1% TFA）-ACN]；B%：16%-46%）純化且並凍乾，得到呈灰白色固體狀之(R )-N -(1-(5-(2-((二甲基胺基)甲基)苯基)噻吩-2-基)乙基)-4-異丙基-6,7-二甲氧基呔

-1-胺（10.3 mg，20.4%產率，99.0%純度，三氟乙酸鹽）。LCMS [M+1]: 491.3。Step B: To ( R )-4-chloro-N-(1-(5-(2-((dimethylamino)methyl)phenyl)thiophen-2-yl)ethyl at 0°C )-6,7-Dimethoxy

-1-amine (40.0 mg, 82.8 µmol, 1.00 equivalent) and iron(III) acetone (80.0 mg, 226 µmol, 2.74 equivalent) in THF (1.00 mL) and 1-methyl-2-pyrrolidone ( Add isopropyl magnesium chloride (3.00 M in THF, 600 µL, 21.7 equivalents) to the solution in 0.01 mL) dropwise. After the addition, the reaction mixture was stirred at 25°C for 10 minutes. The reaction mixture was quenched by adding saturated ammonium chloride solution (5.00 mL), and extracted with ethyl acetate (1.00 mL×3). The combined organic layer was washed with brine (2.00 mL×2), dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by preparative HPLC (column: Phenomenex luna C18 150×25 mm×10 um; mobile phase: [water (0.1% TFA)-ACN]; B%: 16%-46%) and frozen Dry to obtain (R ) -N -(1-(5-(2-((dimethylamino)methyl)phenyl)thiophen-2-yl)ethyl)-4-iso as an off-white solid Propyl-6,7-dimethoxy

-1-amine (10.3 mg, 20.4% yield, 99.0% purity, trifluoroacetate). LCMS [M+1]: 491.3.

¹ H NMR (400 MHz, CD ₃ OD) δ = 8.11 (s, 1H), 7.68 (s, 1H), 7.66-7.63 (m, 1H), 7.56-7.47 (m, 3H), 7.26-7.21 (m , 1H), 7.04 (d, J = 3.6 Hz, 1H), 5.73-5.60 (m, 1H), 4.52 (s, 2H), 4.12 (s, 3H), 4.11 (s, 3H), 3.97-3.88 ( m, 1H), 2.73 (s, 6H), 1.91 (d, J = 6.8 Hz, 3H), 1.53-1.42 (m, 6H).

SFC conditions: column: Chiralcel OD-3 50×4.6 mm inner diameter, 3 um; mobile phase: phase A is CO2, phase B is MeOH (0.05% DEA); gradient dissolution: MeOH (0.05% DEA) in 5% To 40% CO2; flow rate: 3 ml/min; detector: PDA; column temperature: 35°C; back pressure: 100 Bar.

N -(1-(5-(2-((二甲基胺基)甲基)苯基)噻吩-2-基)乙基)-4-乙基-6,7-二甲氧基呔

-1-胺 ¹ H NMR (400 MHz, CD₃ OD) δ 8.08 (s, 1H), 7.69 - 7.64 (m, 2H), 7.58 - 7.48 (m, 3H), 7.25 - 7.23 (m, 1H), 7.06 - 7.02 (m, 1H), 5.73 (q,J = 6.8 Hz, 1H), 4.53 (s, 2H), 4.15 (s, 3H), 4.13 (s, 3H), 3.39 - 3.34 (m, 3H), 2.75 (s, 6H), 1.90 (d,J = 6.9 Hz, 3H), 1.48 (t,J = 7.5 Hz, 3H)。LCMS [M+1]: 477.3。 5-3

(R )-6,7-二甲氧基-4-甲基-N -(1-(2-甲基-3-((甲基胺基)甲基)苯基)乙基)呔

-1-胺 ¹ H NMR (400 MHz, CD₃ OD) δ = 8.08 (s, 1H), 7.56 - 7.62 (m, 2H), 7.22 - 7.35 (m, 2H), 5.50 - 5.61 (m, 1H), 4.34 - 4.42 (m, 1H), 4.21 - 4.28 (m, 1H), 4.16 (s, 3 H), 4.09 (s, 3H), 2.85 (s, 3 H), 2.79 (s, 3H), 2.55 (s, 3H), 1.69 (d,J = 6.8 Hz, 3H)。LCMS [M+1]⁺ = 381.2。 實例5-4 (R )-N -(1-(5-(2-((二甲基胺基)甲基)苯基)噻吩-2-基)乙基)-6,7-二甲氧基-4-(三氟甲基)呔

-1-胺

Following the teaching of General Reaction Scheme I and the procedure of Preparation Example 5-1, the following compounds of formula (I) as shown in Table 5 were prepared, Example 5-2-5-3: Table 5 Example # structure Spectral data 5-2

N -(1-(5-(2-((dimethylamino)methyl)phenyl)thiophen-2-yl)ethyl)-4-ethyl-6,7-dimethoxy

-1-amine ¹ H NMR (400 MHz, CD ₃ OD) δ 8.08 (s, 1H), 7.69-7.64 (m, 2H), 7.58-7.48 (m, 3H), 7.25-7.23 (m, 1H), 7.06-7.02 ( m, 1H), 5.73 (q, J = 6.8 Hz, 1H), 4.53 (s, 2H), 4.15 (s, 3H), 4.13 (s, 3H), 3.39-3.34 (m, 3H), 2.75 (s , 6H), 1.90 (d, J = 6.9 Hz, 3H), 1.48 (t, J = 7.5 Hz, 3H). LCMS [M+1]: 477.3. 5-3

( R )-6,7-Dimethoxy-4-methyl- N -(1-(2-methyl-3-((methylamino)methyl)phenyl)ethyl)

-1-amine ¹ H NMR (400 MHz, CD ₃ OD) δ = 8.08 (s, 1H), 7.56-7.62 (m, 2H), 7.22-7.35 (m, 2H), 5.50-5.61 (m, 1H), 4.34-4.42 (m, 1H), 4.21-4.28 (m, 1H), 4.16 (s, 3 H), 4.09 (s, 3H), 2.85 (s, 3 H), 2.79 (s, 3H), 2.55 (s, 3H) ), 1.69 (d, J = 6.8 Hz, 3H). LCMS [M+1] ⁺ = 381.2. Example 5-4 ( R ) -N -(1-(5-(2-((dimethylamino)methyl)phenyl)thiophen-2-yl)ethyl)-6,7-dimethoxy -4-(trifluoromethyl)

-1-amine

Step A: Under a nitrogen atmosphere at -78°C, to a solution of 2-bromo-4,5-dimethoxybenzoic acid (0.30 g, 1.15 mmol, 1.00 equivalent) in tetrahydrofuran (20.0 mL) was added positive Butyl lithium (1.60 M, 1.72 mL, 2.40 equivalents). After stirring for 1 hour at -78°C, ethyl 2,2,2-trifluoroacetate (163 mg, 1.15 mmol, 159 µL, 1.00 equivalent) was added dropwise at the same temperature. The mixture was stirred at -78°C for 1 hour, warmed to 20°C, and stirred at 20°C for 3 hours. The reaction mixture was poured into ice water (20.0 mL), and extracted with ethyl acetate (20.0 mL×3). The combined organic phase was washed with brine (20.0 mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 5/1 to 0/1) to obtain 4,5-dimethoxy-2-(2 ,2,2-Trifluoroacetyl)benzoic acid (0.10 g, 30.9% yield). LCMS [M+1] ⁺ = 279.0.

¹ H NMR (400 MHz, CDCl ₃ ) δ = 7.30 (s, 1H), 7.11 (s, 1H), 4.03 (s, 3H), 3.98 (s, 3H).

-1(2H )-酮（80.0 mg，粗製）。LCMS [M+1]⁺ = 316.1。Step B: Add 4,5-dimethoxy-2-(2,2,2-trifluoroacetoxy)benzoic acid (0.10 g, 359 µmol, 1.00 equivalent) in ethanol (10.0 mL) at 20°C _{Add NH 2} NH ₂ ·H ₂ O (180 mg, 3.59 mmol, 175 µL, 10.0 equivalent) to the suspension in ). The mixture was stirred at 100°C for 3 hours. After completion, the reaction mixture was concentrated under reduced pressure to obtain 6,7-dimethoxy-4-(trifluoromethyl) as a yellow solid.

-1(2 H )-ketone (80.0 mg, crude). LCMS [M+1] ⁺ = 316.1.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 7.70 (s, 1H), 7.15 (s, 1H), 3.98 (s, 3H), 3.96 (s, 3H).

-1(2H )-酮（300 mg，1.09 mmol，1.00當量）於POCl₃ （4.95 g，32.3 mmol，3.00 mL，29.5當量）中之溶液中添加N,N- 二異丙基乙胺（707 mg，5.47 mmol，953 µL，5.00當量）。將混合物在100℃下攪拌30分鐘。在減壓下濃縮反應混合物，得到殘餘物。隨後用乙酸乙酯（10.0 mL）稀釋，倒入冰水（10.0 mL）中，用乙酸乙酯（10.0 mL×3）萃取。將合併之有機層經無水硫酸鈉乾燥，過濾，且在減壓下濃縮，得到殘餘物。將殘餘物藉由管柱層析法（SiO₂ ，石油醚/乙酸乙酯＝10/1至1/1）純化，得到呈黃色固體狀之1-氯-6,7-二甲氧基-4-(三氟甲基)呔

（50.2 mg，171 µmol，15.7%產率）。LCMS [M+1]⁺ = 293.0。Step C: Add 6,7-dimethoxy-4-(trifluoromethyl) to 6,7-dimethoxy-4-(trifluoromethyl) at 25°C

-1(2 H )-ketone (300 mg, 1.09 mmol, 1.00 equivalent) in POCl ₃ (4.95 g, 32.3 mmol, 3.00 mL, 29.5 equivalent) was added N,N -diisopropylethylamine ( 707 mg, 5.47 mmol, 953 µL, 5.00 equivalent). The mixture was stirred at 100°C for 30 minutes. The reaction mixture was concentrated under reduced pressure to obtain a residue. Then it was diluted with ethyl acetate (10.0 mL), poured into ice water (10.0 mL), and extracted with ethyl acetate (10.0 mL×3). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 10/1 to 1/1) to obtain 1-chloro-6,7-dimethoxy- as a yellow solid 4-(Trifluoromethyl)

(50.2 mg, 171 µmol, 15.7% yield). LCMS [M+1] ⁺ = 293.0.

¹ H NMR (500 MHz, CDCl ₃ ) δ = 7.60 (s, 1H), 7.44 (d, J = 1.0 Hz, 1H), 4.15 (s, 3H), 4.12 (s, 3H).

（49.3 mg，168 µmol，1.00當量）於DMSO（1.00 mL）中之溶液中添加N,N- 二異丙基乙胺（87.1 mg，674 µmol，117 µL，4.00當量）及氟化鉀（2.94 mg，50.5 µmol，1.18 µL，0.30當量）。完成後，將反應混合物過濾，且將殘餘物藉由製備型HPLC（管柱：Agela DuraShell C18 150×25 mm×5 um；移動相：A相：[水（0.05% NH₃ H₂ O+10 mM NH₄ HCO₃ ）]，B相：乙腈；B%：60%-90%）純化，得到呈白色固體狀之(R )-N -(1-(5-(2-((二甲基胺基)甲基)苯基)噻吩-2-基)乙基)-6,7-二甲氧基-4-(三氟甲基)呔

-1-胺（4.51 mg，8.72 µmol，5.18%產率，99.9%純度）。LCMS [M+1]⁺ = 517.1。Step D: To ( R )-1-(5-(2-((dimethylamino)methyl)phenyl)thiophen-2-yl)ethan-1-amine (50.0 mg, 168 µmol, 1.00 equivalent , HCl) and 1-chloro-6,7-dimethoxy-4-(trifluoromethyl)

(49.3 mg, 168 µmol, 1.00 equivalent) in DMSO (1.00 mL) was added N,N -diisopropylethylamine (87.1 mg, 674 µmol, 117 µL, 4.00 equivalent) and potassium fluoride (2.94 mg, 50.5 µmol, 1.18 µL, 0.30 equivalent). After completion, the reaction mixture was filtered, and the residue was subjected to preparative HPLC (column: Agela DuraShell C18 150×25 mm×5 um; mobile phase: phase A: [water (0.05% NH ₃ H ₂ O+10 mM NH ₄ HCO ₃ )], phase B: acetonitrile; B%: 60%-90%) purified to obtain ( R ) -N -(1-(5-(2-((dimethyl (Amino)methyl)phenyl)thiophen-2-yl)ethyl)-6,7-dimethoxy-4-(trifluoromethyl)

-1-amine (4.51 mg, 8.72 µmol, 5.18% yield, 99.9% purity). LCMS [M+1] ⁺ = 517.1.

-1-基)呔

-1-胺

¹ H NMR (500 MHz, CDCl ₃ ) δ = 7.51-7.46 (m, 1H), 7.43 (dd, J = 1.5, 7.0 Hz, 1H), 7.36 (d, J = 1.5 Hz, 1H), 7.35-7.28 (m, 2H), 7.13 (s, 2H), 6.99 (br s, 1H), 6.20-6.13 (m, 1H), 5.39 (br s, 1H), 4.08 (s, 3H), 4.07 (s, 3H) ), 3.53 (br s, 2H), 2.25 (br s, 6H), 1.87 (d, J = 6.5 Hz, 3H). Example 6-1 ( R )-4-methyl- N -(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-7-(4-methylpiper

-1-base) 呔

-1-amine

烷（50.0 mL）中之混合物脫氣且用氮氣沖洗3次，隨後將反應混合物在氮氣氛圍下在80℃下攪拌10小時。將反應混合物冷卻至25℃，藉由加水（50.0 mL）淬滅，隨後用乙酸乙酯（50.0 mL×3）萃取。將合併之有機層用鹽水（20.0 mL×3）洗滌，經硫酸鈉乾燥，過濾且在減壓下濃縮，得到呈黃色油狀之5-溴-2-(1-乙氧基乙烯基)苯甲酸甲酯（6.00 g，粗製），其直接用於下一步。Step A: Combine 5-bromo-2-iodobenzoic acid methyl ester (5.00 g, 14.7 mmol, 1.00 equivalent), tributyl(1-ethoxyvinyl)stannane (5.60 g, 15.4 mmol, 5.20 mL, 1.05 equivalent) and Pd(PPh ₃ ) ₂ Cl ₂ (309 mg, 440 µmol, 0.03 equivalent) in two

The mixture in alkane (50.0 mL) was degassed and flushed with nitrogen 3 times, then the reaction mixture was stirred at 80°C for 10 hours under a nitrogen atmosphere. The reaction mixture was cooled to 25°C, quenched by adding water (50.0 mL), and then extracted with ethyl acetate (50.0 mL×3). The combined organic layer was washed with brine (20.0 mL×3), dried over sodium sulfate, filtered and concentrated under reduced pressure to give 5-bromo-2-(1-ethoxyvinyl)benzene as a yellow oil Methyl formate (6.00 g, crude), which was used directly in the next step.

Step B: Add aqueous hydrochloric acid (10%, 25.0 mL) to a solution of methyl 5-bromo-2-(1-ethoxyvinyl)benzoate (6.00 g, crude) in tetrahydrofuran solution (50.0 mL) . The reaction mixture was stirred at 20°C for 1 hour. Water (50.0 mL) was added to the reaction mixture, and the aqueous layer was extracted with ethyl acetate (100 mL×3). The combined organic layer was washed with brine (30.0 mL×2), dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 1/0 to 50/1) to obtain methyl 2-acetyl 5-bromobenzoate ( 2.50 g, 67.0% yield).

¹ H NMR (400 MHz, CDCl ₃ ) δ = 7.97 (d, J = 2.0 Hz, 1H), 7.70 (dd, J = 2.0, 8.2 Hz, 1H), 7.32 (d, J = 8.4 Hz, 1H), 3.91 (s, 3H), 2.53 (s, 3H).

-1(2H )-酮（0.70 g，2.93 mmol，50.2%產率）。LCMS [M+1]⁺ : 239.0。Step C: Add hydrazine hydrate (876 mg, 17.5 mmol, 851 µL, 3.00) to a solution of methyl 2-acetyl-5-bromobenzoate (1.50 g, 5.83 mmol, 1.00 equivalent) in ethanol (30.0 mL) equivalent). The reaction mixture was stirred at 95°C for 30 minutes. The reaction mixture was then cooled to 25°C and concentrated under reduced pressure to obtain a residue. The residue was wet-milled with ethanol for 10 minutes to obtain a suspension, the suspension was filtered, the filter cake was collected and dried in vacuo to obtain 7-bromo-4-methylbenzene as a white solid

-1( 2H )-one (0.70 g, 2.93 mmol, 50.2% yield). LCMS [M+1] ⁺ : 239.0.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 12.57 (br s, 1H), 8.32 (d, J = 2.0 Hz, 1H), 8.11 (dd, J = 2.0, 8.4 Hz, 1H), 7.88 ( d, J = 8.4 Hz, 1H), 2.50 (s, 3H).

-1-醇（1.00 g，4.18 mmol，1.00當量）、1-甲基哌

（628 mg，6.27 mmol，696 µL，1.50當量）、RuPhos（195 mg，418 µmol，0.10當量）、Pd₂ (dba)₃ （192 mg，209 µmol，0.05當量）及t- BuOK（1 M於THF中，8.37 mL，2.00當量）於二

烷（10.0 mL）中之混合物脫氣且用N₂ 沖洗3次，且隨後將混合物在N₂ 氛圍下在110℃下攪拌1.5小時。將反應混合物藉由添加水（20 mL）來淬滅，隨後用EtOAc（10 mL×3）萃取。將合併之有機層用鹽水（5 mL×2）洗滌，經Na₂ SO₄ 乾燥，過濾，且在減壓下濃縮，得到殘餘物。將粗產物與用EtOAc（3 mL）濕磨10分鐘，得到呈黃色固體狀之4-甲基-7-(4-甲基哌

-1-基)呔

-1(2H )-酮（800 mg，3.10 mmol，74.0%產率）。LCMS [M+1]⁺ : 259.1。Step D: Add 7-bromo-4-methyl

-1-ol (1.00 g, 4.18 mmol, 1.00 equivalent), 1-methylpiper

(628 mg, 6.27 mmol, 696 µL, 1.50 equivalent), RuPhos (195 mg, 418 µmol, 0.10 equivalent), Pd ₂ (dba) ₃ (192 mg, 209 µmol, 0.05 equivalent) and t- BuOK (1 M in THF, 8.37 mL, 2.00 equivalent) in two

The mixture in alkane (10.0 mL) was degassed and _{flushed with N 2} three times, and then the mixture was stirred at 110° C. under an _{N 2 atmosphere for 1.5 hours.} The reaction mixture was quenched by adding water (20 mL), followed by extraction with EtOAc (10 mL×3). The combined organic layer was washed with brine (5 mL×2), _{dried over Na 2} SO ₄ , filtered, and concentrated under reduced pressure to obtain a residue. The crude product was wet triturated with EtOAc (3 mL) for 10 minutes to give 4-methyl-7-(4-methylpiperidine) as a yellow solid

-1-base) 呔

-1(2 H )-ketone (800 mg, 3.10 mmol, 74.0% yield). LCMS [M+1] ⁺ : 259.1.

¹ H NMR (400MHz, DMSO- d ₆ ) δ = 12.13 (s, 1H), 7.74 (d, J = 8.8 Hz, 1H), 7.56 (dd, J = 2.8, 9.0 Hz, 1H), 7.50 (d, J = 2.6 Hz, 1H), 3.40-3.34 (m, 4H), 2.49-2.45 (m, 4H), 2.43 (s, 3H), 2.23 (s, 3H).

-1-基)呔

-1(2H )-酮（100 mg，387 µmol，1.00當量）於三氯氧磷（1.61 g，10.5 mmol，976 µL，27.1當量）中之溶液。將混合物在110℃下攪拌16小時。隨後將反應混合物冷卻至25℃，且在真空下濃縮，得到殘餘物。將殘餘物溶於水（10.0 mL）中，且用飽和硫酸鈉調節至pH＝9，且用乙酸乙酯（5.00 mL×2）萃取。將有機層經無水硫酸鈉乾燥且在真空下濃縮，得到呈褐色固體狀之4-氯-1-甲基-6-(4-甲基哌

-1-基)呔

（70.0 mg，粗製），其無需純化即可直接使用。LCMS [M+1]⁺ : 277.1。Step E: Add 4-methyl-7-(4-methylpiper

-1-base) 呔

-1(2 H )-ketone (100 mg, 387 µmol, 1.00 equivalent) in phosphorus oxychloride (1.61 g, 10.5 mmol, 976 µL, 27.1 equivalent). The mixture was stirred at 110°C for 16 hours. The reaction mixture was then cooled to 25°C and concentrated under vacuum to give a residue. The residue was dissolved in water (10.0 mL), adjusted to pH=9 with saturated sodium sulfate, and extracted with ethyl acetate (5.00 mL×2). The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum to obtain 4-chloro-1-methyl-6-(4-methylpiperidine) as a brown solid

-1-base) 呔

(70.0 mg, crude), it can be used directly without purification. LCMS [M+1] ⁺ : 277.1.

-1-基)呔

（60.0 mg，217 µmo，1.00當量）及(R )-1-(2-甲基-3-(三氟甲基)苯基)乙-1-胺（48.5 mg，238 µmol，1.10當量）於二甲基亞碸（3.00 mL）中之溶液中添加氟化銫（98.8 mg，650 µmol，24.0 µL，3.00當量）及N,N- 二異丙基乙胺（140 mg，1.08 mmol，189 µL，5.00當量）。隨後將混合物在120℃下攪拌16小時。隨後將反應混合物倒入水（1.50 ml）中，且藉由製備型HPLC（管柱：Boston Green ODS 150×30 mm×5 um；移動相：[水（0.1% TFA）-ACN]；B%：25%-45%，10分鐘）純化。將產物藉由製備型HPLC（管柱：Aegla DuraShell C18 150×25 mm×5 um；移動相：[水（0.05% NH₃ H₂ O+10mM NH₄ HCO₃ ）-ACN]；B%：38%-68%，10分鐘）進一步純化，得到呈白色固體狀之(R) -4-甲基-N -(1-(2-甲基-3-(三氟甲基)苯基)乙基)-7-(4-甲基哌

-1-基)呔

-1-胺（17.0 mg，3.83 µmol，17.6%產率，99.9%純度）。LCMS [M+1]⁺ : 444.1。Step F: To -chloro-1-methyl-6-(4-methylpiper

-1-base) 呔

(60.0 mg, 217 µmo, 1.00 equivalent) and ( R )-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl-1-amine (48.5 mg, 238 µmol, 1.10 equivalent) in Add cesium fluoride (98.8 mg, 650 µmol, 24.0 µL, 3.00 equivalents) and N,N -diisopropylethylamine (140 mg, 1.08 mmol, 189 µL) to the solution in dimethyl sulfide (3.00 mL) , 5.00 equivalent). The mixture was then stirred at 120°C for 16 hours. The reaction mixture was then poured into water (1.50 ml) and subjected to preparative HPLC (column: Boston Green ODS 150×30 mm×5 um; mobile phase: [water (0.1% TFA)-ACN]; B% : 25%-45%, 10 minutes) purification. The product was subjected to preparative HPLC (column: Aegla DuraShell C18 150×25 mm×5 um; mobile phase: [water (0.05% NH ₃ H ₂ O+10mM NH ₄ HCO ₃ )-ACN]; B%: 38 %-68%, 10 minutes) for further purification to obtain ( R) -4-methyl- N -(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl as a white solid )-7-(4-methylpiper

-1-base) 呔

-1-amine (17.0 mg, 3.83 µmol, 17.6% yield, 99.9% purity). LCMS [M+1] ⁺ : 444.1.

啉基吡啶并[3,4-d]嗒

-1-胺

¹ H NMR (500 MHz, CD ₃ OD) δ = 7.91 (d, J = 9.50 Hz, 1H), 7.70 (d, J = 8.50 Hz, 1H), 7.55-7.63 (m, 2H), 7.48 (d, J = 8.00 Hz, 1H), 7.23 (t, J = 7.50 Hz, 1H), 5.75-5.70 (m, 1H), 3.55 (br s, 4H), 2.68 (br t, J = 5.00 Hz, 4H), 2.59-2.63 (m, 6H), 2.40 (s, 3H), 1.63 (d, J = 7.00 Hz, 3H). Example 6-2 ( R )-4-methyl- N -(1-(5-(2-((methylamino)methyl)phenyl)thiophen-2-yl)ethyl)-7-

Hydroxypyrido[3,4-d]

-1-amine

_{Step A: Add SOCl 2} (7.25 g, 60.9 mmol, 4.42 mL, 1.20 to a solution of 5-bromo-2-chloroisonicotinic acid (12.0 g, 50.6 mmol, 1.00 equivalent) in MeOH (100 mL) dropwise Equivalent), then the mixture was heated to 75°C and stirred for 8 hours. The reaction mixture was then concentrated under reduced pressure to obtain a residue. The residue was diluted with EtOAc (100 mL), washed with saturated NaHCO ₃ (100 mL), _{dried over Na 2} SO ₄ , filtered, and concentrated under reduced pressure to give 5-bromo-2-chloro as a yellow oil Methyl isonicotinate (12.0 g, crude). LCMS [M+1] ⁺ : 252.0.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 8.78 (s, 1H), 7.89 (s, 1H), 3.91 (s, 3H).

烷（110mL）中之溶液脫氣且用N₂ 沖洗3次，且隨後將混合物在N₂ 氛圍下在80℃下加熱16小時。隨後將反應混合物藉由加水（400 mL）來淬滅，且隨後用EtOAc（150 mL×3）萃取。將合併之有機層用鹽水（200 mL）洗滌，經Na₂ SO₄ 乾燥，過濾，且在減壓下濃縮，得到呈黃色油狀之2-氯-5-(1-乙氧基乙烯基)異菸酸甲酯（10.6 g，粗製）。Step B: Combine 5-bromo-2-chloroisonicotinic acid methyl ester (11.0 g, 43.92 mmol, 1.00 equivalent), tributyl(1-ethoxyvinyl)stannane (16.7 g, 46.1 mmol, 15.6 mL , 1.05 equivalent) and Pd(PPh ₃ ) ₂ Cl ₂ (1.23 g, 1.76 mmol, 0.04 equivalent) in two

The solution in alkane (110 mL) was degassed and _{flushed with N 2} three times, and then the mixture was heated at 80° C. under an _{N 2 atmosphere for 16 hours.} The reaction mixture was then quenched by adding water (400 mL), and then extracted with EtOAc (150 mL×3). The combined organic layer was washed with brine (200 mL), _{dried over Na 2} SO ₄ , filtered, and concentrated under reduced pressure to give 2-chloro-5-(1-ethoxyvinyl) as a yellow oil Methyl isonicotinate (10.6 g, crude).

Step C: Add HCl (102 g, 280 mmol, 100 mL, 10% purity in water, 6.38 equivalents), and the mixture was stirred at 20°C for 16 hours. _{The reaction mixture was then quenched by adding NaHCO 3} (300 mL) at 0° C., and then extracted with EtOAc (100 mL×3). The combined organic layers were washed with brine (100 mL), dried over Na ₂ SO _4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 1/0 to 3/1) to obtain 5-acetyl-2-chloroisonicotinic acid methyl as a white solid Ester (4.50 g, 21.1 mmol, 48.0% yield).

¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 8.98 (s, 1H), 7.85 (s, 1H), 3.84 (s, 3H), 2.61 (s, 3H).

-1(2H )-酮（0.85 g，粗製）。LCMS [M+1]⁺ : 196.1。Step D: To a solution of methyl 5-acetyl-2-chloroisonicotinate (1.00 g, 4.68 mmol, 1.00 equivalent) in EtOH (15.0 mL), add hydrazine hydrate (703 mg, 14.0 mmol, 683 µL) , 3.00 equivalents), the mixture was stirred at 95°C for 30 minutes. The reaction mixture was then filtered, and the filter cake was concentrated under reduced pressure to obtain a residue to obtain 7-chloro-4-methylpyrido[3,4- d ]ba as a white solid

-1(2 H )-ketone (0.85 g, crude). LCMS [M+1] ⁺ : 196.1.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 9.20 (s, 1H), 8.10 (s, 1H), 2.58 (s, 3H).

-1(2H )-酮（750 mg，3.83 mmol，1.00當量）、

啉（668 mg，7.67 mmol，675 µL，2.00當量）於二

烷（10.0 mL）、t BuOK（1.00 M於THF中，11.5 mL，3.00當量）、RuPhos（179 mg，383 µmol，0.10當量）及Pd₂ (dba)₃ （176 mg，192 µmol，0.05當量）中之溶液脫氣，且用氮氣沖洗3次，且將混合物在氮氣氛圍下在110℃下攪拌3小時。將反應混合物過濾，且將濾液在減壓下濃縮，得到殘餘物。將殘餘物藉由製備型HPLC（管柱：Phenomenex luna C18（250×70 mm，15 um）；移動相：[水（0.05% HCl）-ACN]；B%：10%-40%）純化，得到呈白色固體狀之4-甲基-7-

啉基吡啶并[3,4-d ]嗒

-1(2H )-酮（500 mg，2.03 mmol，49.2%產率）。LCMS [M+1]⁺ : 247.0。Step E: Add 7-chloro-4-methylpyrido[3,4- d ]

-1(2 H )-ketone (750 mg, 3.83 mmol, 1.00 equivalent),

Pyridine (668 mg, 7.67 mmol, 675 µL, 2.00 equivalent) in two

Alkane (10.0 mL), t BuOK (1.00 M in THF, 11.5 mL, 3.00 equivalents), RuPhos (179 mg, 383 µmol, 0.10 equivalents), and Pd ₂ (dba) ₃ (176 mg, 192 µmol, 0.05 equivalents) The solution in the medium was degassed and flushed with nitrogen 3 times, and the mixture was stirred at 110°C for 3 hours under a nitrogen atmosphere. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by preparative HPLC (column: Phenomenex luna C18 (250×70 mm, 15 um); mobile phase: [water (0.05% HCl)-ACN]; B%: 10%-40%), 4-methyl-7- as a white solid

Hydroxypyrido[3,4- d ]

-1( 2H )-ketone (500 mg, 2.03 mmol, 49.2% yield). LCMS [M+1] ⁺ : 247.0.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 12.26 (s, 1H), 8.89 (s, 1H), 7.23 (s, 1H), 3.75-3.70 (m, 4H), 3.68-3.63 (m, 4H), 2.46 (s, 3H).

啉基吡啶并[3,4-d ]嗒

-1(2H )-酮（500 mg，2.03 mmol，1.00當量）於POCl₃ （6.23 g，40.6 mmol，3.77 mL，20.0當量）中之溶液在110℃下攪拌3小時。隨後將反應混合物在減壓下濃縮以移除POCl₃ 。將殘餘物用H₂ O（100 mL）稀釋，且隨後用NaHCO₃ 固體調節至pH＝8，且隨後用乙酸乙酯（50.0 mL×3）萃取。將合併之有機層用鹽水（50.0 mL）洗滌，經Na₂ SO₄ 乾燥，過濾，且在減壓下濃縮，得到呈黃色固體狀之4-(1-氯-4-甲基吡啶并[3,4-d]嗒

-7-基)

啉（500 mg，粗製）。LCMS [M+1]⁺ : 264.9。Step F: Add -methyl-7-

Hydroxypyrido[3,4- d ]

A solution of -1(2 H )-ketone (500 mg, 2.03 mmol, 1.00 equivalent) in POCl ₃ (6.23 g, 40.6 mmol, 3.77 mL, 20.0 equivalent) was stirred at 110°C for 3 hours. The reaction mixture was then concentrated under reduced pressure to remove POCl ₃ . The residue was diluted with H ₂ O (100 mL), and then _{adjusted to pH=8 with NaHCO 3} solid, and then extracted with ethyl acetate (50.0 mL×3). The combined organic layer was washed with brine (50.0 mL), _{dried over Na 2} SO ₄ , filtered, and concentrated under reduced pressure to give 4-(1-chloro-4-methylpyrido[3] as a yellow solid ,4-d]

-7-base)

Morinoline (500 mg, crude). LCMS [M+1] ⁺ : 264.9.

¹ H NMR (400 MHz, CDCl ₃ ) δ = 9.13 (s, 1H), 6.89 (s, 1H), 3.92-3.86 (m, 4H), 3.81-3.75 (m, 4H), 2.91 (s, 3H) .

-7-基)

啉（50.0 mg，189 µmol，1.00當量）及(R )-(2-(5-(1-胺基乙基)噻吩-2-基)苯甲基)(甲基)胺甲酸第三丁酯（65.5 mg，189 µmol，1.00當量）於二甲基亞碸（2.00 mL）中之混合物中添加氟化銫（57.4 mg，378 µmol，13.9 µL，2.00當量）及N,N- 二異丙基乙胺（48.8 mg，378 µmol，65.8 µL，2.00當量）。將混合物在130℃下攪拌3小時，隨後冷卻至室溫，且將水（30.0 mL）添加至反應混合物中，且用乙酸乙酯（3×20 mL）萃取。將合併之有機層用鹽水（20.0 mL）洗滌，經硫酸鈉乾燥，過濾，且在減壓下濃縮，得到殘餘物。將殘餘物藉由製備型HPLC（管柱：Agela DuraShell C18 150×25 mm×5 um，使用水（0.04% NH₄ OH+10 mM NH₄ HCO₃ ）及乙腈作為溶離劑。移動相A：水（0.04% NH₃ H₂ O+10 mM NH₄ HCO₃ ）-ACN，移動相B：乙腈。梯度：24%-54% B）純化，得到呈黃色固體狀之(R )-甲基(2-(5-(1-((4-甲基-7-

啉基吡啶并[3,4-d ]嗒

-1-基)胺基)乙基)噻吩-2-基)苯甲基)胺甲酸第三丁酯（20.0 mg，34.8 µmol，18.4%產率）。LCMS [M+1]⁺ : 575.4。Step G: In the glove box, add 4-(1-chloro-4-methylpyrido[3,4-d]

-7-base)

Morinoline (50.0 mg, 189 µmol, 1.00 equivalent) and ( R )-(2-(5-(1-aminoethyl)thiophen-2-yl)benzyl)(methyl)carbamic acid tert-butyl ester (65.5 mg, 189 µmol, 1.00 equivalent) Cesium fluoride (57.4 mg, 378 µmol, 13.9 µL, 2.00 equivalent) and N,N -diisopropyl were added to the mixture in dimethyl sulfenite (2.00 mL) Ethylamine (48.8 mg, 378 µmol, 65.8 µL, 2.00 equivalents). The mixture was stirred at 130°C for 3 hours, then cooled to room temperature, and water (30.0 mL) was added to the reaction mixture, and extracted with ethyl acetate (3×20 mL). The combined organic layer was washed with brine (20.0 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was subjected to preparative HPLC (column: Agela DuraShell C18 150×25 mm×5 um, using water (0.04% NH ₄ OH+10 mM NH ₄ HCO ₃ ) and acetonitrile as the eluent. Mobile phase A: water (0.04% NH ₃ H ₂ O+10 mM NH ₄ HCO ₃ )-ACN, mobile phase B: acetonitrile. Gradient: 24%-54% B) Purification, to obtain ( R )-methyl (2) as a yellow solid -(5-(1-((4-methyl-7-

Hydroxypyrido[3,4- d ]

-1-yl)amino)ethyl)thiophen-2-yl)benzyl)t-butyl carbamate (20.0 mg, 34.8 µmol, 18.4% yield). LCMS [M+1] ⁺ : 575.4.

¹ H NMR (400 MHz, CD ₃ OD) δ = 9.25 (s, 1H), 7.42 (s, 1H), 7.17-7.37 (m, 5H), 7.10 (d, J = 3.6 Hz, 1H), 6.86 ( br s, 1H), 5.59-5.68 (m, 1H), 4.46-4.52 (m, 2H), 3.92 (br s, 4H), 3.76-3.84 (m, 4H), 2.84 (s, 3H), 2.70 ( s, 3H), 1.80 (d, J = 7.2 Hz, 3H), 1.45 (br s, 9H).

啉基吡啶并[3,4-d ]嗒

-1-基)胺基)乙基)噻吩-2-基)苯甲基)胺甲酸第三丁酯（20.0 mg，34.8 µmol，1.00當量）於二氯甲烷（1.00 mL）中之混合物中添加三氟乙酸（0.20 mL）。完成後，將混合物濃縮且將殘餘物藉由製備型HPLC（管柱：Agela DuraShell C18 150×25 mm×5 um，使用水（0.04% NH₃ H₂ O+10 mM NH₄ HCO₃ ）及乙腈作為溶離劑。移動相A：水（0.04% NH₄ OH+10 mM NH₄ HCO₃ ），移動相B：乙腈。梯度：35%-65% B）純化，得到呈白色固體狀之(R )-4-甲基-N -(1-(5-(2-((甲基胺基)甲基)苯基)噻吩-2-基)乙基)-7-

啉基吡啶并[3,4-d ]嗒

-1-胺（4 mg，8.43 µmol，24.2%產率）。LCMS [M+1]⁺ : 475.3。Step H: To ( R )-methyl(2-(5-(1-((4-methyl-7-

Hydroxypyrido[3,4- d ]

-1-yl)amino)ethyl)thiophen-2-yl)benzyl) tertiary butyl carbamate (20.0 mg, 34.8 µmol, 1.00 equivalent) was added to the mixture in dichloromethane (1.00 mL) Trifluoroacetic acid (0.20 mL). After completion, the mixture was concentrated and the residue was subjected to preparative HPLC (column: Agela DuraShell C18 150×25 mm×5 um, using water (0.04% NH ₃ H ₂ O+10 mM NH ₄ HCO ₃ ) and acetonitrile As a dissolving agent, mobile phase A: water (0.04% NH ₄ OH+10 mM NH ₄ HCO ₃ ), mobile phase B: acetonitrile. Gradient: 35%-65% B) Purified to obtain ( R ) as a white solid -4-methyl- N -(1-(5-(2-((methylamino)methyl)phenyl)thiophen-2-yl)ethyl)-7-

Hydroxypyrido[3,4- d ]

-1-amine (4 mg, 8.43 µmol, 24.2% yield). LCMS [M+1] ⁺ : 475.3.

¹ H NMR (400 MHz, CD ₃ OD) δ = 9.04 (s, 1H), 7.43 (br d, J = 6.4 Hz, 1H), 7.25-7.36 (m, 4H), 7.08 (d, J = 2.8 Hz , 1H), 6.92 (d, J = 3.2 Hz, 1H), 5.83 (br d, J = 6.8 Hz, 1H), 3.80-3.86 (m, 6H), 3.70-3.77 (m, 4H), 2.69 (s , 3H), 2.28 (s, 3H), 1.79 (d, J = 6.8 Hz, 3H).

(R )-4-甲基-N -(1-(5-(2-((甲基胺基)甲基)苯基)噻吩-2-基)乙基)-7-

啉基呔

-1-胺 ¹ H NMR (400 MHz, CD₃ OD) δ= 7.93 (d,J = 9.2 Hz, 1H), 7.58 (dd,J = 2.8, 9.2 Hz, 1H), 7.51 (d,J = 2.0 Hz, 1H), 7.44 - 7.39 (m, 1H), 7.35 - 7.24 (m, 3H), 7.08 (dd,J = 0.8, 3.2 Hz, 1H), 6.91 (d,J = 3.6 Hz, 1H), 5.88 (q,J = 7.2 Hz, 1H), 3.90 - 3.85 (m, 4H), 3.80 (s, 2H), 3.46 - 3.40 (m, 4H), 2.67 (s, 3H), 2.25 (s, 3H), 1.80 (d,J = 7.2 Hz, 3H).LCMS [M+1]⁺ : 474.2。 6-4

(R )-4-甲基-N -(1-(2-甲基-3-(三氟甲基)苯基)乙基)-7-(哌

-1-基)呔

-1-胺 ¹ H NMR (400 MHz, CD₃ OD) δ 7.82-7.94 (m, 1H), 7.69 (d,J = 8.0 Hz, 1H), 7.55-7.62 (m, 2H), 7.47 (d,J = 7.6 Hz, 1H), 7.22 (t,J = 7.6 Hz, 1H), 5.70 (q,J = 6.8 Hz, 1H), 3.49 - 3.42 (m, 4H), 3.05 - 2.98 (m, 4H), 2.59 (s, 3H), 2.58 (s, 3H), 1.62 (d,J = 7.2 Hz, 3H)。LCMS [M+1]⁺ : 430.3。 6-5

(R )-N -(1-(3-胺基-5-(三氟甲基)苯基)乙基)-4-甲基-7-

啉基呔

-1-胺 ¹ H NMR (400 MHz, CD₃ OD) δ = 8.18 (d,J = 9.2 Hz, 1H), 7.85 (br s, 3H), 7.73 (d,J = 8.4 Hz, 1H), 7.54 (s, 1H), 5.38 (q,J = 6.4 Hz, 1H), 3.91-3.86 (m, 4H), 3.73 (br s, 4H), 2.79 (s, 3H), 1.78 (d,J = 7.2 Hz, 3H)。LCMS [M+1]⁺ : 432.2。 6-6

(R )-N -(1-(5-(3-氟-2-((甲基胺基)甲基)苯基)噻吩-2-基)乙基)-4-甲基-7-

啉基呔

-1-胺 ¹ H NMR (400 MHz, CD₃ OD) δ = 7.93 (dd,J = 2.0, 9.2 Hz, 1H), 7.61-7.56 (m, 1H), 7.51 (d,J = 2.0 Hz, 1H), 7.32 - 7.26 (m, 1H), 7.18 (d,J = 7.6 Hz, 1H), 7.12 - 7.06 (m, 2H), 6.98 (d,J = 3.6 Hz, 1H), 5.89 (q,J = 6.8 Hz, 1H), 3.91 - 3.85 (m, 4H), 3.80 (s, 2H), 3.47 - 3.40 (m, 4H), 2.67 (s, 3H), 2.21 (s, 3H), 1.80 (d,J = 6.8 Hz, 3H)。LCMS [M+1]⁺ : 492.0。 6-7

(R )-1-甲基-4-(1-甲基-4-((1-(2-甲基-3-(三氟甲基)苯基)乙基)胺基)呔

-6-基)哌

-2-酮 ¹ H NMR (400 MHz, CD₃ OD) δ 8.40 (d,J = 8.8 Hz, 1H), 7.87-7.97 (m, 3H), 7.73 (d,J = 7.6 Hz, 1H), 7.44-7.52 (m, 1H), 5.74 (q,J = 6.8 Hz, 1H), 4.51 (s, 2H), 4.14-4.25 (m, 2H), 3.87 (t,J = 5.2 Hz, 2H), 3.30 (s, 3H), 2.97 (s, 3H), 2.83 (s, 3H), 1.88 (d,J = 7.2 Hz, 3H); LCMS [M+1]⁺ : 458.2。 6-8

(R )-4-甲基-N -(1-(2-甲基-3-((甲基胺基)甲基)苯基)乙基)-7-

啉基呔

-1-胺 ¹ H NMR (500 MHz, CD₃ OD) δ = 8.17 (d,J = 9.5 Hz, 1H), 7.69 - 7.78 (m, 2H), 7.57 (dd,J = 6.5, 1.0 Hz, 1H), 7.28 - 7.31 (m, 1H), 7.22 - 7.27 (m, 1H), 5.55 (q,J = 7.0 Hz, 1H), 4.40 - 4.36 (m, 1H), 4.20 - 4.28 (m, 1H), 3.86 - 3.93 (m, 4H), 3.64 - 3.72 (m, 4H), 2.78 (d,J = 4.5 Hz, 6H), 2.55 (s, 3 H), 1.66 (d,J = 7.0 Hz, 3H)。LCMS [M+1]⁺ = 406.1。 6-9

(R )-4-甲基-N -(1-(2-甲基-3-(三氟甲基)苯基)乙基)-7-(哌

-1-基)吡啶并[3,4-d ]嗒

-1-胺 ¹ H NMR (400 MHz, CD₃ OD) δ = 9.30 (s, 1H), 7.74 (s, 1H), 7.69 (d,J = 8.0 Hz, 1H), 7.54 (d,J = 8.0 Hz, 1H), 7.28 (t,J = 7.6 Hz, 1H), 5.51 (q,J = 7.2 Hz, 1H), 4.20 - 4.28 (m, 4H), 3.40-3.46 (m, 4H), 2.81 (s, 3H), 2.61 (s, 3H), 1.66 (d,J = 6.8 Hz, 3H); LCMS [M+1]⁺ : 431.3。 6-10

(R )-7-(6,7-二氫吡唑并[1,5-a]吡

-5(4H )-基)-4-甲基-N -(1-(2-甲基-3-(三氟甲基)苯基)乙基)呔

-1-胺 ¹ H NMR (400 MHz, CD₃ OD) δ 8.22 (d,J = 9.2 Hz, 1H), 7.90 - 7.81 (m, 2H), 7.70 (d,J = 7.6 Hz, 1H), 7.56 - 7.50 (m, 2H), 7.32-7.23 (m, 1H), 6.29 (d,J = 2.0 Hz, 1H), 5.54 (q,J = 6.8 Hz, 1H), 5.01 (s, 2H), 4.44 - 4.37 (m, 2H), 4.31 - 4.24 (m, 2H), 2.77 (s, 3H), 2.63 (s, 3H), 1.68 (d,J = 7.2 Hz, 3H)。 LCMS [M+1]⁺ : 467.2。 6-11

(R )-環丙基(4-(1-甲基-4-((1-(2-甲基-3-(三氟甲基)苯基)乙基)胺基)呔

-6-基)哌

-1-基)甲酮 ¹ H NMR (400 MHz, CD₃ OD) δ 8.17 (d,J = 9.2 Hz, 1H), 7.78 - 7.65 (m, 3H), 7.52 (d,J = 7.6 Hz, 1H), 7.31 - 7.22 (m, 1H), 5.52 (q,J = 6.8 Hz, 1H), 4.05 (br s, 2H), 3.90 - 3.76 (m, 6H), 2.75 (s, 3H), 2.62 (s, 3H), 2.08 - 1.97 (m, 1H), 1.66 (d,J = 6.8 Hz, 3H), 0.97 - 0.84 (m, 4H)。 LCMS [M+1]⁺ : 498.2。 6-12

(R )-4-甲基-N -(1-(2-甲基-3-(三氟甲基)苯基)乙基)-7-

啉基吡啶并[3,4-d ]嗒

-1-胺 ¹ H NMR (400 MHz, CD₃ OD) δ = 9.00 (s, 1H), 7.67 (br d,J = 7.6 Hz, 1H), 7.48 (br d,J = 7.2 Hz, 1H), 7.33 (s, 1H), 7.23 (br t,J = 8.0 Hz, 1H), 5.67 (q,J = 6.8 Hz, 1H), 3.89 - 3.81 (m, 4H), 3.80 - 3.71 (m, 4H), 2.63 - 2.58 (m, 6H), 1.61 (d,J = 6.8 Hz, 3H)。LCMS [M+1]⁺ : 432.2。 6-13

(R )-N -(1-(5-(3-氟-2-((甲基胺基)甲基)苯基)噻吩-2-基)乙基)-4-甲基-7-

啉基吡啶并[3,4-d ]嗒

-1-胺 ¹ H NMR (400 MHz, CD₃ OD) δ = 9.03 (d,J = 0.4 Hz, 1H), 7.33 - 7.26 (m, 1H), 7.25 (s, 1H), 7.19 - 7.16 (m, 1H), 7.13 - 7.06 (m, 2H), 6.99 (d,J = 3.6 Hz, 1H), 5.85 (q,J = 6.8 Hz, 1H), 3.84 - 3.79 (m, 6H), 3.76 - 3.72 (m, 4H), 2.69 (s, 3H), 2.23 (s, 3H), 1.79 (d,J = 7.2 Hz, 3H)。LCMS [M+1]⁺ : 493.2。 6-14

(R )-N -(1-(3-氟-5-(三氟甲基)苯基)乙基)-4-甲基-7-

啉基吡啶并[3,4-d ]嗒

-1-胺 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.03 (s, 1H), 7.63 (s, 1H), 7.59 - 7.48 (m, 3H), 7.39 (s, 1H), 5.48 (t,J = 6.8 Hz, 1H), 3.86 - 3.76 (m, 4H), 3.75-3.66 (m, 4H), 2.58 (s, 3H), 1.61 (d,J = 6.8 Hz, 3H)。LCMS [M+1]⁺ : 436.3。 6-15

(R )-3-(1-((4-甲基-7-

啉基呔

-1-基)胺基)乙基)苯甲腈 ¹ H NMR (400 MHz, CD₃ OD) δ = 8.20 - 8.14 (m, 1H), 7.84 - 7.77 (m, 1H), 7.82 - 7.69 (m, 3H), 7.60 (br d,J = 7.6 Hz, 1H), 7.54 - 7.47 (m, 1H), 5.29 (q,J = 7.2 Hz, 1H), 3.92 - 3.88 (m, 4H), 3.73 - 3.65 (m, 4H), 2.78 (s, 3H), 1.72 (d,J = 7.2 Hz, 3H) 。LCMS [M+1]⁺ : 374.2。 6-16

(R )-3-(1-((4-甲基-7-

啉基吡啶并[3,4-d ]嗒

-1-基)胺基)乙基)苯甲腈 ¹ H NMR (400 MHz, MeOD-d ₄ ) δ = 9.25 (s, 1H), 7.84 - 7.73 (m, 2H), 7.61 (d,J = 7.6 Hz, 1H), 7.55 - 7.46 (m, 2H), 5.26 (q,J = 6.8 Hz, 1H), 4.00 - 3.94 (m, 1H), 4.04 - 3.93 (m, 3H), 3.88 - 3.83 (m, 2H), 3.88 - 3.81 (m, 1H), 3.88 - 3.80 (m, 1H), 2.80 (s, 3H), 1.71 (d,J = 7.2 Hz, 3H)。LCMS [M+1]⁺ : 375.1。 6-17

(R )-3-氟-5-(1-((4-甲基-7-

啉基吡啶并[3,4-d]嗒

-1-基)胺基)乙基)苯甲腈 ¹ H NMR (400 MHz, CD₃ OD) δ = 9.01 (d,J = 0.8 Hz, 1H), 7.63 (t,J = 1.2 Hz, 1H), 7.51 (dt,J = 9.6, 2.0 Hz, 1H), 7.32-7.37 (m, 1H), 7.29 (d,J = 0.4 Hz, 1H), 5.39 (q,J = 7.2 Hz, 1H), 3.81-3.86 (m, 4H), 3.74-3.79 (m, 4H), 2.64 (s, 3H), 1.66 (d,J = 7.2 Hz, 3H)。LCMS [M+1]⁺ : 393.2。 6-18

(R )-N -(1-(3-氯-2-甲基苯基)乙基)-4-甲基-7-

啉基吡啶并[3,4-d ]嗒

-1-胺 ¹ H NMR (400 MHz, CD₃ OD) δ = 9.23 (s, 1H), 7.53 (s, 1H), 7.35 (d,J = 8.0 Hz, 1H), 7.25 (d,J = 7.6 Hz, 1H), 7.13 - 7.06 (m, 1H), 5.43 (q,J = 6.8 Hz, 1H), 3.99 - 3.93 (m, 4H), 3.89 - 3.80 (m, 4H), 2.78 (s, 3H), 2.54 (s, 3H), 1.64 (d,J = 6.8 Hz, 3H)。LCMS [M+1]⁺ : 398.2。 6-19

(R )-4-甲基-N -(1-(2-甲基-3-(甲基磺醯基)苯基)乙基)-7-

啉基吡啶并[3,4-d ]嗒

-1-胺 ¹ H NMR (400 MHz, DMSO-d ₆ )δ = 9.01 (s, 1H), 7.79 (dd,J = 12.4, 8.0 Hz, 2H), 7.55 (d,J = 6.8 Hz, 1H), 7.45-7.36 (m, 2H), 5.71-5.61 (m, 1H), 3.82-3.77 (m, 4H), 3.76-3.67 (m, 4H), 3.26 (s, 3H), 2.80 (s, 3H), 2.57 (s, 3H), 1.56 (d,J = 6.8 Hz, 3H)。LCMS [M+1]⁺ : 442.1。 實例7-1 4-甲基-N -((R )-1-(5-(2-((甲基胺基)甲基)苯基)噻吩-2-基)乙基)-7-(((S )-四氫呋喃-3-基)氧基)呔

-1-胺

Following the teachings of general reaction schemes II and IV and the procedures of preparation examples 6-1, 6-2, 10-1 and 10-2, the following compounds of formula (I) as shown in Table 6 were prepared, examples 6-3 to 6-19: Table 6 Example # structure Spectral data 6-3

( R )-4-methyl- N -(1-(5-(2-((methylamino)methyl)phenyl)thiophen-2-yl)ethyl)-7-

Linyl

-1-amine ¹ H NMR (400 MHz, CD ₃ OD) δ = 7.93 (d, J = 9.2 Hz, 1H), 7.58 (dd, J = 2.8, 9.2 Hz, 1H), 7.51 (d, J = 2.0 Hz, 1H) , 7.44-7.39 (m, 1H), 7.35-7.24 (m, 3H), 7.08 (dd, J = 0.8, 3.2 Hz, 1H), 6.91 (d, J = 3.6 Hz, 1H), 5.88 (q, J = 7.2 Hz, 1H), 3.90-3.85 (m, 4H), 3.80 (s, 2H), 3.46-3.40 (m, 4H), 2.67 (s, 3H), 2.25 (s, 3H), 1.80 (d, J = 7.2 Hz, 3H). LCMS [M+1] ⁺ : 474.2. 6-4

( R )-4-methyl- N -(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-7-(piper

-1-base) 呔

-1-amine ¹ H NMR (400 MHz, CD ₃ OD) δ 7.82-7.94 (m, 1H), 7.69 (d, J = 8.0 Hz, 1H), 7.55-7.62 (m, 2H), 7.47 (d, J = 7.6 Hz , 1H), 7.22 (t, J = 7.6 Hz, 1H), 5.70 (q, J = 6.8 Hz, 1H), 3.49-3.42 (m, 4H), 3.05-2.98 (m, 4H), 2.59 (s, 3H), 2.58 (s, 3H), 1.62 (d, J = 7.2 Hz, 3H). LCMS [M+1] ⁺ : 430.3. 6-5

( R ) -N -(1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)-4-methyl-7-

Linyl

-1-amine ¹ H NMR (400 MHz, CD ₃ OD) δ = 8.18 (d, J = 9.2 Hz, 1H), 7.85 (br s, 3H), 7.73 (d, J = 8.4 Hz, 1H), 7.54 (s, 1H ), 5.38 (q, J = 6.4 Hz, 1H), 3.91-3.86 (m, 4H), 3.73 (br s, 4H), 2.79 (s, 3H), 1.78 (d, J = 7.2 Hz, 3H). LCMS [M+1] ⁺ : 432.2. 6-6

( R ) -N -(1-(5-(3-Fluoro-2-((methylamino)methyl)phenyl)thiophen-2-yl)ethyl)-4-methyl-7-

Linyl

-1-amine ¹ H NMR (400 MHz, CD ₃ OD) δ = 7.93 (dd, J = 2.0, 9.2 Hz, 1H), 7.61-7.56 (m, 1H), 7.51 (d, J = 2.0 Hz, 1H), 7.32- 7.26 (m, 1H), 7.18 (d, J = 7.6 Hz, 1H), 7.12-7.06 (m, 2H), 6.98 (d, J = 3.6 Hz, 1H), 5.89 (q, J = 6.8 Hz, 1H ), 3.91-3.85 (m, 4H), 3.80 (s, 2H), 3.47-3.40 (m, 4H), 2.67 (s, 3H), 2.21 (s, 3H), 1.80 (d, J = 6.8 Hz, 3H). LCMS [M+1] ⁺ : 492.0. 6-7

( R )-1-methyl-4-(1-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)

-6-yl)piperidine

-2-one ¹ H NMR (400 MHz, CD ₃ OD) δ 8.40 (d, J = 8.8 Hz, 1H), 7.87-7.97 (m, 3H), 7.73 (d, J = 7.6 Hz, 1H), 7.44-7.52 (m , 1H), 5.74 (q, J = 6.8 Hz, 1H), 4.51 (s, 2H), 4.14-4.25 (m, 2H), 3.87 (t, J = 5.2 Hz, 2H), 3.30 (s, 3H) , 2.97 (s, 3H), 2.83 (s, 3H), 1.88 (d, J = 7.2 Hz, 3H); LCMS [M+1] ⁺ : 458.2. 6-8

( R )-4-methyl- N -(1-(2-methyl-3-((methylamino)methyl)phenyl)ethyl)-7-

Linyl

-1-amine ¹ H NMR (500 MHz, CD ₃ OD) δ = 8.17 (d, J = 9.5 Hz, 1H), 7.69-7.78 (m, 2H), 7.57 (dd, J = 6.5, 1.0 Hz, 1H), 7.28- 7.31 (m, 1H), 7.22-7.27 (m, 1H), 5.55 (q, J = 7.0 Hz, 1H), 4.40-4.36 (m, 1H), 4.20-4.28 (m, 1H), 3.86-3.93 ( m, 4H), 3.64-3.72 (m, 4H), 2.78 (d, J = 4.5 Hz, 6H), 2.55 (s, 3 H), 1.66 (d, J = 7.0 Hz, 3H). LCMS [M+1] ⁺ = 406.1. 6-9

( R )-4-methyl- N -(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-7-(piper

-1-yl)pyrido[3,4- d ]

-1-amine ¹ H NMR (400 MHz, CD ₃ OD) δ = 9.30 (s, 1H), 7.74 (s, 1H), 7.69 (d, J = 8.0 Hz, 1H), 7.54 (d, J = 8.0 Hz, 1H) , 7.28 (t, J = 7.6 Hz, 1H), 5.51 (q, J = 7.2 Hz, 1H), 4.20-4.28 (m, 4H), 3.40-3.46 (m, 4H), 2.81 (s, 3H), 2.61 (s, 3H), 1.66 (d, J = 6.8 Hz, 3H); LCMS [M+1] ⁺ : 431.3. 6-10

( R )-7-(6,7-dihydropyrazolo[1,5-a]pyridine

-5(4 H )-yl)-4-methyl- N -(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)

-1-amine ¹ H NMR (400 MHz, CD ₃ OD) δ 8.22 (d, J = 9.2 Hz, 1H), 7.90-7.81 (m, 2H), 7.70 (d, J = 7.6 Hz, 1H), 7.56-7.50 (m , 2H), 7.32-7.23 (m, 1H), 6.29 (d, J = 2.0 Hz, 1H), 5.54 (q, J = 6.8 Hz, 1H), 5.01 (s, 2H), 4.44-4.37 (m, 2H), 4.31-4.24 (m, 2H), 2.77 (s, 3H), 2.63 (s, 3H), 1.68 (d, J = 7.2 Hz, 3H). LCMS [M+1] ⁺ : 467.2. 6-11

( R )-Cyclopropyl(4-(1-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)

-6-yl)piperidine

-1-yl) ketone ¹ H NMR (400 MHz, CD ₃ OD) δ 8.17 (d, J = 9.2 Hz, 1H), 7.78-7.65 (m, 3H), 7.52 (d, J = 7.6 Hz, 1H), 7.31-7.22 (m , 1H), 5.52 (q, J = 6.8 Hz, 1H), 4.05 (br s, 2H), 3.90-3.76 (m, 6H), 2.75 (s, 3H), 2.62 (s, 3H), 2.08-1.97 (m, 1H), 1.66 (d, J = 6.8 Hz, 3H), 0.97-0.84 (m, 4H). LCMS [M+1] ⁺ : 498.2. 6-12

( R )-4-methyl- N -(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-7-

Hydroxypyrido[3,4- d ]

-1-amine ¹ H NMR (400 MHz, CD ₃ OD) δ = 9.00 (s, 1H), 7.67 (br d, J = 7.6 Hz, 1H), 7.48 (br d, J = 7.2 Hz, 1H), 7.33 (s, 1H), 7.23 (br t, J = 8.0 Hz, 1H), 5.67 (q, J = 6.8 Hz, 1H), 3.89-3.81 (m, 4H), 3.80-3.71 (m, 4H), 2.63-2.58 ( m, 6H), 1.61 (d, J = 6.8 Hz, 3H). LCMS [M+1] ⁺ : 432.2. 6-13

( R ) -N -(1-(5-(3-Fluoro-2-((methylamino)methyl)phenyl)thiophen-2-yl)ethyl)-4-methyl-7-

Hydroxypyrido[3,4- d ]

-1-amine ¹ H NMR (400 MHz, CD ₃ OD) δ = 9.03 (d, J = 0.4 Hz, 1H), 7.33-7.26 (m, 1H), 7.25 (s, 1H), 7.19-7.16 (m, 1H), 7.13-7.06 (m, 2H), 6.99 (d, J = 3.6 Hz, 1H), 5.85 (q, J = 6.8 Hz, 1H), 3.84-3.79 (m, 6H), 3.76-3.72 (m, 4H) , 2.69 (s, 3H), 2.23 (s, 3H), 1.79 (d, J = 7.2 Hz, 3H). LCMS [M+1] ⁺ : 493.2. 6-14

( R ) -N -(1-(3-Fluoro-5-(trifluoromethyl)phenyl)ethyl)-4-methyl-7-

Hydroxypyrido[3,4- d ]

-1-amine ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 9.03 (s, 1H), 7.63 (s, 1H), 7.59-7.48 (m, 3H), 7.39 (s, 1H), 5.48 (t, J = 6.8 Hz, 1H), 3.86-3.76 (m, 4H), 3.75-3.66 (m, 4H), 2.58 (s, 3H), 1.61 (d, J = 6.8 Hz, 3H). LCMS [M+1] ⁺ : 436.3. 6-15

( R )-3-(1-((4-methyl-7-

Linyl

-1-yl)amino)ethyl)benzonitrile ¹ H NMR (400 MHz, CD ₃ OD) δ = 8.20-8.14 (m, 1H), 7.84-7.77 (m, 1H), 7.82-7.69 (m, 3H), 7.60 (br d, J = 7.6 Hz, 1H), 7.54-7.47 (m, 1H), 5.29 (q, J = 7.2 Hz, 1H), 3.92-3.88 (m, 4H), 3.73-3.65 (m, 4H), 2.78 (s, 3H), 1.72 (d, J = 7.2 Hz, 3H). LCMS [M+1] ⁺ : 374.2. 6-16

( R )-3-(1-((4-methyl-7-

Hydroxypyrido[3,4- d ]

-1-yl)amino)ethyl)benzonitrile ¹ H NMR (400 MHz, MeOD- d ₄ ) δ = 9.25 (s, 1H), 7.84-7.73 (m, 2H), 7.61 (d, J = 7.6 Hz, 1H), 7.55-7.46 (m, 2H) , 5.26 (q, J = 6.8 Hz, 1H), 4.00-3.94 (m, 1H), 4.04-3.93 (m, 3H), 3.88-3.83 (m, 2H), 3.88-3.81 (m, 1H), 3.88 -3.80 (m, 1H), 2.80 (s, 3H), 1.71 (d, J = 7.2 Hz, 3H). LCMS [M+1] ⁺ : 375.1. 6-17

( R )-3-Fluoro-5-(1-((4-methyl-7-

Hydroxypyrido[3,4-d]

-1-yl)amino)ethyl)benzonitrile ¹ H NMR (400 MHz, CD ₃ OD) δ = 9.01 (d, J = 0.8 Hz, 1H), 7.63 (t, J = 1.2 Hz, 1H), 7.51 (dt, J = 9.6, 2.0 Hz, 1H) , 7.32-7.37 (m, 1H), 7.29 (d, J = 0.4 Hz, 1H), 5.39 (q, J = 7.2 Hz, 1H), 3.81-3.86 (m, 4H), 3.74-3.79 (m, 4H ), 2.64 (s, 3H), 1.66 (d, J = 7.2 Hz, 3H). LCMS [M+1] ⁺ : 393.2. 6-18

( R ) -N -(1-(3-Chloro-2-methylphenyl)ethyl)-4-methyl-7-

Hydroxypyrido[3,4- d ]

-1-amine ¹ H NMR (400 MHz, CD ₃ OD) δ = 9.23 (s, 1H), 7.53 (s, 1H), 7.35 (d, J = 8.0 Hz, 1H), 7.25 (d, J = 7.6 Hz, 1H) , 7.13-7.06 (m, 1H), 5.43 (q, J = 6.8 Hz, 1H), 3.99-3.93 (m, 4H), 3.89-3.80 (m, 4H), 2.78 (s, 3H), 2.54 (s , 3H), 1.64 (d, J = 6.8 Hz, 3H). LCMS [M+1] ⁺ : 398.2. 6-19

( R )-4-methyl- N -(1-(2-methyl-3-(methylsulfonyl)phenyl)ethyl)-7-

Hydroxypyrido[3,4- d ]

-1-amine ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 9.01 (s, 1H), 7.79 (dd, J = 12.4, 8.0 Hz, 2H), 7.55 (d, J = 6.8 Hz, 1H), 7.45-7.36 (m, 2H), 5.71-5.61 (m, 1H), 3.82-3.77 (m, 4H), 3.76-3.67 (m, 4H), 3.26 (s, 3H), 2.80 (s, 3H), 2.57 (s , 3H), 1.56 (d, J = 6.8 Hz, 3H). LCMS [M+1] ⁺ : 442.1. Example 7-1 4-methyl- N -(( R )-1-(5-(2-((methylamino)methyl)phenyl)thiophen-2-yl)ethyl)-7-( (( S )-Tetrahydrofuran-3-yl)oxy)

-1-amine

Step A: Add 1-(4-(benzyloxy)-2-hydroxyphenyl)ethan-1-one (5.00 g, 20.6 mmol, 1.00 equivalent) and pyridine (4.90 g, 61.9 mmol, 5.00 mL, 3.00 equivalents) was slowly added dropwise to the mixture of DCM (100 mL) trifluoromethanesulfonyl trifluoromethanesulfonate (11.7 g, 41.3 mmol, 6.81 mL, 2.00 equivalents) ). The reaction mixture was then stirred at 20°C for 16 hours. The reaction mixture was poured into water (100 mL) and stirred for 5 minutes. The aqueous phase was extracted with DCM (50.0 mL×3). The combined organic phase was washed with brine (50.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain a residue. The residue was purified by silica gel chromatography (SiO ₂ , petroleum ether/ethyl acetate = 10/1 to 3/1) to obtain 2-acetyl-5-(benzyloxy) as a yellow solid Phenyl triflate (7.40 g, 17.8 mmol, 86.2% yield, 90% purity). LCMS [M+1] ⁺ : 374.8.

¹ H NMR (400 MHz, CDCl ₃ ) δ = 7.85 (d, J = 8.8 Hz, 1H), 7.44-7.36 (m, 5H), 7.03 (dd, J = 2.4, 8.8 Hz, 1H), 6.90 (d , J = 2.4 Hz, 1H), 5.14 (s, 2H), 2.60 (s, 3H).

Step B: Under a nitrogen atmosphere at 20°C, add 2-acetyl-5-(benzyloxy)phenyl trifluoromethanesulfonate (13.0 g, 34.7 mmol, 1.00 equivalent) and 1,1- To a solution of bis(diphenylphosphino)ferrocene (1.93 g, 3.47 mmol, 0.10 equivalent) in DMF (100 mL) and methanol (10.0 mL) was added triethylamine (17.6 g, 174 mmol, 24.2 mL, 5.00 equivalents) and palladium(II) acetate (780 mg, 3.47 mmol, 0.10 equivalents). The reaction mixture was heated to 80°C and stirred for 16 hours under an atmosphere of carbon monoxide (50 Psi). The mixture was then cooled to 15°C and concentrated under reduced pressure at 40°C to obtain a residue. The residue was poured into water (100 mL) and stirred for 5 minutes. The aqueous phase was extracted with ethyl acetate (50.0 mL×3). The combined organic phase was washed with brine (50.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel chromatography (SiO ₂ , petroleum ether/ethyl acetate = 5/1 to 4/1) to obtain 2-acetyl-5-(benzyloxy) as a yellow solid Methyl benzoate (5.60 g, 16.9 mmol, 48.8% yield, 86% purity). LCMS [M+1] ⁺ : 285.0.

¹ H NMR (400 MHz, CDCl ₃ ) δ = 7.58 (d, J = 8.8 Hz, 1H), 7.44-7.35 (m, 5H), 7.26 (d, J = 2.8 Hz, 1H), 7.08 (dd, J = 2.4, 8.4 Hz, 1H), 5.14 (s, 2H), 3.91 (s, 3H), 2.53 (s, 3H).

-1(2H )-酮（4.00 g，粗製）。LCMS [M+1]⁺ : 267.0。Step C: At 25℃, slowly drop by drop to a solution of methyl 2-acetyl-5-(benzyloxy)benzoate (4.60 g, 16.2 mmol, 1.00 equivalent) in ethanol (50.0 mL) Hydrazine hydrate (2.48 g, 48.5 mmol, 2.41 mL, 98% purity, 3.00 equivalents) was added, and then the reaction mixture was stirred at 95°C for 30 minutes. The reaction mixture was cooled to 15°C, and poured into ice water (w/w=1/1) (100 mL), and stirred for 5 minutes to obtain a suspension. The resulting suspension was filtered, and the filter cake was collected and dried under reduced pressure to obtain 7-(benzyloxy)-4-methyl as a yellow solid

-1(2 H )-ketone (4.00 g, crude). LCMS [M+1] ⁺ : 267.0.

-1(2H )-酮（860 mg，3.23 mmol，1.00當量）分批添加至三氯氧磷（14.2 g，92.6 mmol，8.60 mL，28.7當量）中，隨後將反應混合物在120℃下攪拌3小時。將混合物冷卻至25℃，且在減壓下濃縮，得到殘餘物。將殘餘物緩慢倒入冰水（50.0 mL）中，且用飽和碳酸氫鈉水溶液（50.0 mL）調節至pH＝8，且攪拌5分鐘。用乙酸乙酯（50.0 mL×3）萃取水相。將合併之有機相用鹽水（50.0 mL）洗滌，經無水硫酸鈉乾燥，過濾，且在減壓下濃縮，得到為呈白色固體狀之6 6-(苯甲氧基)-4-氯-1-甲基呔

（740 mg，粗製）。LCMS [M+1]⁺ : 284.9。Step D: At 25 ℃, 7-(benzyloxy)-4-methyl

-1(2 H )-ketone (860 mg, 3.23 mmol, 1.00 equivalent) was added to phosphorus oxychloride (14.2 g, 92.6 mmol, 8.60 mL, 28.7 equivalent) in batches, and then the reaction mixture was stirred at 120°C 3 hours. The mixture was cooled to 25°C and concentrated under reduced pressure to obtain a residue. The residue was slowly poured into ice water (50.0 mL), and adjusted to pH=8 with saturated sodium bicarbonate aqueous solution (50.0 mL), and stirred for 5 minutes. The aqueous phase was extracted with ethyl acetate (50.0 mL×3). The combined organic phase was washed with brine (50.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 6 6-(benzyloxy)-4-chloro-1 as a white solid -Methyl

(740 mg, crude). LCMS [M+1] ⁺ : 284.9.

（120 mg，421 µmol，1.00當量）及(R)-(2-(5-(1-胺基乙基)噻吩-2-基)苯甲基)(甲基)胺甲酸第三丁酯（102 mg，295 µmol，0.70當量）於二甲基亞碸（1.00 mL）中之溶液中添加氟化銫（192 mg，1.26 mmol，46.6 µL，3.00當量）。隨後將混合物在130℃下攪拌16小時，且將混合物用乙酸乙酯（30.0 mL）稀釋。將合併之有機部分用鹽水（3×8 mL）洗滌，經硫酸鈉乾燥，過濾，且在減壓下蒸發溶劑，得到殘餘物。將殘餘物藉由矽膠管柱急速層析法12 g純化，用石油醚/乙酸乙酯＝0-100%溶離，得到呈褐色固體狀之(R )-(2-(5-(1-((7-(苯甲氧基)-4-甲基呔

-1-基)胺基)乙基)噻吩-2-基)苯甲基)(甲基)胺甲酸第三丁酯（60.0 mg，44.2 µmol，10.5%產率，43.8%純度）。LCMS [M+1] +: 595.3。Step E: To 6-(benzyloxy)-4-chloro-1-methyl

(120 mg, 421 µmol, 1.00 equivalent) and (R)-(2-(5-(1-aminoethyl)thiophen-2-yl)benzyl)(methyl)carbamate ( 102 mg, 295 µmol, 0.70 equivalent) cesium fluoride (192 mg, 1.26 mmol, 46.6 µL, 3.00 equivalent) was added to a solution of dimethyl sulfoxide (1.00 mL). The mixture was then stirred at 130°C for 16 hours, and the mixture was diluted with ethyl acetate (30.0 mL). The combined organic portions were washed with brine (3×8 mL), dried over sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to give a residue. The residue was purified by 12 g silica gel column flash chromatography and eluted with petroleum ether/ethyl acetate=0-100% to obtain ( R )-(2-(5-(1-() as a brown solid (7-(benzyloxy)-4-methyl

-1-yl)amino)ethyl)thiophen-2-yl)benzyl)(methyl)tert-butyl carbamate (60.0 mg, 44.2 µmol, 10.5% yield, 43.8% purity). LCMS [M+1] +: 595.3.

-1-基)胺基)乙基)噻吩-2-基)苯甲基)(甲基)胺甲酸第三丁酯（60.0 mg，100 µmol，1.00當量）於甲醇（3.00 mL）中之溶液中添加Pd/C（10.7 mg，10.1 µmol，10%純度，0.10當量）。隨後將混合物在30℃下攪拌3小時。隨後將混合物過濾且將濾餅用甲醇（5.00 mL）及二氯甲烷（10.0 ml）洗滌。將濾液在減壓下濃縮。將粗產物藉由逆相HPLC（管柱：Phenomenex Synergi C18 150×30 mm×4 um；移動相：A相：[水（0.1% TFA）]，B相：乙腈；B%：42%-62%）純化，得到呈白色固體狀之(R )-(2-(5-(1-((7-羥基-4-甲基呔

-1-基)胺基)乙基)噻吩-2-基)苯甲基)(甲基)胺甲酸第三丁酯（15.0 mg，29.7 µmol，29.5%產率）。LCMS [M+1]⁺ : 505.3。Step F: In ( R )-(2-(5-(1-((7-(benzyloxy)-4-methyl

-1-yl)amino)ethyl)thiophen-2-yl)benzyl)(methyl) tert-butyl carbamate (60.0 mg, 100 µmol, 1.00 equivalent) in methanol (3.00 mL) Add Pd/C (10.7 mg, 10.1 µmol, 10% purity, 0.10 equivalent). The mixture was then stirred at 30°C for 3 hours. The mixture was then filtered and the filter cake was washed with methanol (5.00 mL) and dichloromethane (10.0 ml). The filtrate was concentrated under reduced pressure. The crude product was subjected to reverse phase HPLC (column: Phenomenex Synergi C18 150×30 mm×4 um; mobile phase: phase A: [water (0.1% TFA)], phase B: acetonitrile; B%: 42%-62 %) purified to obtain ( R )-(2-(5-(1-((7-hydroxy-4-methyl

-1-yl)amino)ethyl)thiophen-2-yl)benzyl)(methyl)tert-butyl carbamate (15.0 mg, 29.7 µmol, 29.5% yield). LCMS [M+1] ⁺ : 505.3.

-1-基)胺基)乙基)噻吩-2-基)苯甲基)(甲基)胺甲酸第三丁酯（13.0 mg，25.8 µmol，1.00當量）及4-甲基苯磺酸(R )-四氫呋喃-3-酯（9.16 mg，30.9 µmol，1.20當量）於DMF（0.10 mL）中之溶液中添加氟化銫（15.0 mg，98.8 µmol，3.64 µL，3.83當量）。將混合物在90℃下攪拌2小時，隨後倒入水（5.00 mL）中且過濾。將濾液用乙酸乙酯（10 mL×2）萃取，將合併之有機層用鹽水（10.0 mL）洗滌，經無水硫酸鈉乾燥且真空濃縮，得到呈黃色油狀之殘餘物，甲基(2-(5-((R )-1-((4-甲基-7-(((S )-四氫呋喃-3-基)氧基)呔

-1-基)胺基)乙基)噻吩-2-基)苯甲基)胺甲酸第三丁酯（14.8 mg，25.8 µmol，100%產率），其無需進一步純化即可使用。LCMS [M+1]⁺ : 575.3。Step G: To ( R )-(2-(5-(1-((7-hydroxy-4-methyl

-1-yl)amino)ethyl)thiophen-2-yl)benzyl)(methyl) tert-butyl carbamate (13.0 mg, 25.8 µmol, 1.00 equivalent) and 4-methylbenzenesulfonic acid ( R )-Tetrahydrofuran-3-ester (9.16 mg, 30.9 µmol, 1.20 equivalents) in DMF (0.10 mL) was added with cesium fluoride (15.0 mg, 98.8 µmol, 3.64 µL, 3.83 equivalents). The mixture was stirred at 90°C for 2 hours, then poured into water (5.00 mL) and filtered. The filtrate was extracted with ethyl acetate (10 mL×2), the combined organic layer was washed with brine (10.0 mL), dried over anhydrous sodium sulfate and concentrated in vacuo to obtain a yellow oily residue, methyl (2- (5-(( R )-1-((4-methyl-7-((( S )-tetrahydrofuran-3-yl)oxy)

-1-yl)amino)ethyl)thiophen-2-yl)benzyl)tert-butyl carbamate (14.8 mg, 25.8 µmol, 100% yield), which can be used without further purification. LCMS [M+1] ⁺ : 575.3.

-1-基)胺基)乙基)噻吩-2-基)苯甲基)胺甲酸第三丁酯（10.0 mg，17.4 µmol，1.00當量）於二氯甲烷（0.50 mL）中之溶液中添加2,6-二甲吡啶（18.6 mg，173 µmol，20.3 µL，10.0當量），隨後將TMSOTf（19.3 mg，87.0 µmol，15.7 µL，5.00當量）添加至混合物中。將混合物在20℃下攪拌1小時，隨後在氮氣氛圍下蒸發溶劑。將粗產物藉由逆相HPLC（管柱：Agela DuraShell C18 150×25 mm×5 um；移動相：A相：[水（0.05% NH₃ H₂ O+10 mM NH₄ HCO₃ ）]，B相：乙腈；B%：36%-66%）純化，得到呈白色固體狀之4-甲基-N -((R )-1-(5-(2-((甲基胺基)甲基)苯基)噻吩-2-基)乙基)-7-(((S )-四氫呋喃-3-基)氧基)呔

-1-胺（2.20 mg，4.64 µmol，26.6%產率）。LCMS [M+1]⁺ : 475.2。Step H: To methyl (2-(5-(( R )-1-((4-methyl-7-((( S )-tetrahydrofuran-3-yl)oxy)

-1-yl)amino)ethyl)thiophen-2-yl)benzyl) tertiary butyl carbamate (10.0 mg, 17.4 µmol, 1.00 equivalent) in dichloromethane (0.50 mL) 2,6-lutidine (18.6 mg, 173 µmol, 20.3 µL, 10.0 equivalents), and then TMSOTf (19.3 mg, 87.0 µmol, 15.7 µL, 5.00 equivalents) was added to the mixture. The mixture was stirred at 20°C for 1 hour, and then the solvent was evaporated under a nitrogen atmosphere. The crude product was subjected to reverse phase HPLC (column: Agela DuraShell C18 150×25 mm×5 um; mobile phase: phase A: [water (0.05% NH ₃ H ₂ O+10 mM NH ₄ HCO ₃ )], B Phase: Acetonitrile; B%: 36%-66%) to obtain 4-methyl- N -(( R )-1-(5-(2-((methylamino)methyl) as a white solid )Phenyl)thiophen-2-yl)ethyl)-7-((( S )-tetrahydrofuran-3-yl)oxy)

-1-amine (2.20 mg, 4.64 µmol, 26.6% yield). LCMS [M+1] ⁺ : 475.2.

¹ H NMR (400 MHz, CD ₃ OD) δ = 8.02 (d, J = 8.8 Hz, 1H), 7.70 (d, J = 2.4 Hz, 1H), 7.39-7.52 (m, 2H), 7.25-7.38 ( m, 3H), 7.09 (d, J = 2.8 Hz, 1H), 6.92 (d, J = 3.2 Hz, 1H), 5.90 (q, J = 6.8 Hz, 1H), 5.30 (br s, 1H), 3.88 -4.09 (m, 4H), 3.81 (s, 2H), 2.72 (s, 3H), 2.29-2.44 (m, 1H), 2.26 (s, 3H), 2.18 (br dd, J = 5.6, 12.0 Hz, 1H), 1.81 (d, J = 7.2 Hz, 3H).

(R )-4-甲基-N -(1-(2-甲基-3-(三氟甲基)苯基)乙基)-7-(哌啶-4-基氧基)呔

-1-胺 ¹ H NMR (400 MHz, CD₃ OD) δ = 8.35 (d,J = 9.2 Hz, 1H), 8.18 (br d,J = 2.0 Hz, 1H), 7.79 (dd,J = 2.4, 9.2 Hz, 1H), 7.70 (br d,J = 8.4 Hz, 1H), 7.54 (br d,J = 7.6 Hz, 1H), 7.28 (br t,J = 8.4 Hz, 1H), 5.57 (q,J = 7.2 Hz, 1H), 5.17 (br s, 1H), 3.47 (br d,J = 9.2 Hz, 2H), 2.83 (s, 3H), 2.64 (s, 3H), 2.33 (br s, 2H), 2.22 (br s, 2H), 1.68 (d,J = 7.2 Hz, 3H)。LCMS [M+1]⁺ : 445.2。 7-3

4-甲基-N -((R )-1-(2-甲基-3-(三氟甲基)苯基)乙基)-7-(((S )-吡咯啶-3-基)氧基)呔

-1-胺 ¹ H NMR (400 MHz, CD₃ OD) δ = 8.44 - 8.22 (m, 2H), 7.85 - 7.68 (m, 2H), 7.53 (br d,J = 7.6 Hz, 1H), 7.28 (br t,J = 7.6 Hz, 1H), 5.73 (br s, 1H), 5.57 (q,J = 7.2 Hz, 1H), 3.81 - 3.67 (m, 2H), 3.65 - 3.51 (m, 2H), 2.85 (s, 3H), 2.65 (s, 2H), 2.62 - 2.41 (m, 2H), 1.73 (d,J = 6.8 Hz, 3H)。LCMS [M+1]⁺ : 431.3。 7-4

(R )-7-(氮雜環丁烷-3-基氧基)-4-甲基-N -(1-(2-甲基-3-(三氟甲基)苯基)乙基)呔

-1-胺 ¹ H NMR (500 MHz, CD₃ OD) δ 8.38 (d,J = 9.0 Hz, 1H), 8.19 (s, 1H), 7.83 (d,J = 7.8 Hz, 1H), 7.76 (dd,J = 9.0, 2.4 Hz, 1H), 7.52 (d,J = 7.9 Hz, 1H), 7.27 (t,J = 8.0 Hz, 1H), 5.71 - 5.65 (m, 1H), 5.56 (q,J = 7.0 Hz, 1H), 4.85 - 4.77 (m, 2H), 4.34 - 4.26 (m, 2H), 2.84 (s, 3H), 2.63 (s, 3H), 1.73 (d,J = 7.0 Hz, 3H)。LCMS [M+1]⁺ : 417.2。 7-5

4-甲基-N -((R )-1-(2-甲基-3-(三氟甲基)苯基)乙基)-7-(((S )-1-甲基吡咯啶-3-基)氧基)呔

-1-胺 ¹ H NMR (400 MHz, CD₃ OD) δ = 8.40 (br d,J = 8.8 Hz, 1H), 8.30 (br s, 1H), 7.85 - 7.74 (m, 2H), 7.56 (br d,J = 8.0 Hz, 1H), 7.30 (br t,J = 8.0 Hz, 1H), 5.79 - 5.67 (m, 1H), 5.59 (q,J = 6.8 Hz, 1H), 4.36 - 3.89 (m, 2H), 3.72 - 3.45 (m, 2H), 3.17 - 3.06 (m, 3H), 3.01 - 2.91 (m, 1H), 2.87 (s, 3H), 2.70 - 2.61 (m, 3H), 2.61 - 2.37 (m, 1H), 1.74 (br d,J = 6.8 Hz, 3H)。LCMS [M+1]⁺ : 445.2。 7-6

4-甲基-N -((R )-1-(2-甲基-3-(三氟甲基)苯基)乙基)-7-(((S )-吡咯啶-2-基)甲氧基)呔

-1-胺 ¹ H NMR (400 MHz, CD₃ OD) δ = 7.97 (d,J = 9.2 Hz, 1H), 7.80 (d,J = 2.4 Hz, 1H), 7.71 (d,J = 8.0 Hz, 1H), 7.52 - 7.46 (m, 2H), 7.23 (t,J = 7.6 Hz, 1H), 5.73 (q,J = 6.8 Hz, 1H), 4.28 - 4.22 (m, 1H), 4.13 (dd,J = 7.2, 9.2 Hz, 1H), 3.67 - 3.59 (m, 1H), 3.08 - 2.96 (m, 2H), 2.64 (s, 3H), 2.62 (s, 3H), 2.13 - 2.05 (m, 1H), 1.96 - 1.84 (m, 2H), 1.73 - 1.66 (m, 1H), 1.63 (d,J = 7.2 Hz, 3H)。LCMS [M+1]⁺ : 445.2。 7-7

4-甲基-N -((R )-1-(2-甲基-3-(三氟甲基)苯基)乙基)-7-(((R )-吡咯啶-2-基)甲氧基)呔

-1-胺鹽酸鹽 ¹ H NMR (400 MHz, CD₃ OD) δ = 8.40 - 8.38 (m, 2H), 7.91 - 7.78 (m, 2H), 7.55 (br d,J = 7.6 Hz, 1H), 7.30 (br t,J = 7.6 Hz, 1H), 5.60 (q,J = 7.2 Hz, 1H), 4.76 (dd,J = 3.2, 10.8 Hz, 1H), 4.70 - 4.59 (m, 1H), 4.23 (dq,J = 3.2, 8.0 Hz, 1H), 3.55 - 3.41 (m, 2H), 2.88 (s, 3H), 2.66 (s, 3H), 2.41 (dtd,J = 4.8, 7.6, 12.8 Hz, 1H), 2.33 - 2.11 (m, 2H), 2.11 - 2.00 (m, 1H), 1.75 (d,J = 6.8 Hz, 3H)。LCMS [M+1]⁺ : 445.2。 Following the teaching of General Reaction Scheme IV and the procedure of Preparation Example 7-1, the following compounds of formula (I) as shown in Table 7, Examples 7-2 to 7-7 were prepared. Table 7 Example # structure Spectral data 7-2

( R )-4-methyl- N -(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-7-(piperidin-4-yloxy)

-1-amine ¹ H NMR (400 MHz, CD ₃ OD) δ = 8.35 (d, J = 9.2 Hz, 1H), 8.18 (br d, J = 2.0 Hz, 1H), 7.79 (dd, J = 2.4, 9.2 Hz, 1H) ), 7.70 (br d, J = 8.4 Hz, 1H), 7.54 (br d, J = 7.6 Hz, 1H), 7.28 (br t, J = 8.4 Hz, 1H), 5.57 (q, J = 7.2 Hz, 1H), 5.17 (br s, 1H), 3.47 (br d, J = 9.2 Hz, 2H), 2.83 (s, 3H), 2.64 (s, 3H), 2.33 (br s, 2H), 2.22 (br s , 2H), 1.68 (d, J = 7.2 Hz, 3H). LCMS [M+1] ⁺ : 445.2. 7-3

4-methyl- N -(( R )-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-7-((( S )-pyrrolidin-3-yl) Oxy)

-1-amine ¹ H NMR (400 MHz, CD ₃ OD) δ = 8.44-8.22 (m, 2H), 7.85-7.68 (m, 2H), 7.53 (br d, J = 7.6 Hz, 1H), 7.28 (br t, J = 7.6 Hz, 1H), 5.73 (br s, 1H), 5.57 (q, J = 7.2 Hz, 1H), 3.81-3.67 (m, 2H), 3.65-3.51 (m, 2H), 2.85 (s, 3H) ), 2.65 (s, 2H), 2.62-2.41 (m, 2H), 1.73 (d, J = 6.8 Hz, 3H). LCMS [M+1] ⁺ : 431.3. 7-4

( R )-7-(azetidin-3-yloxy)-4-methyl- N -(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl) Hum

-1-amine ¹ H NMR (500 MHz, CD ₃ OD) δ 8.38 (d, J = 9.0 Hz, 1H), 8.19 (s, 1H), 7.83 (d, J = 7.8 Hz, 1H), 7.76 (dd, J = 9.0 , 2.4 Hz, 1H), 7.52 (d, J = 7.9 Hz, 1H), 7.27 (t, J = 8.0 Hz, 1H), 5.71-5.65 (m, 1H), 5.56 (q, J = 7.0 Hz, 1H ), 4.85-4.77 (m, 2H), 4.34-4.26 (m, 2H), 2.84 (s, 3H), 2.63 (s, 3H), 1.73 (d, J = 7.0 Hz, 3H). LCMS [M+1] ⁺ : 417.2. 7-5

4-methyl- N -(( R )-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-7-((( S )-1-methylpyrrolidine- 3-yl)oxy)

-1-amine ¹ H NMR (400 MHz, CD ₃ OD) δ = 8.40 (br d, J = 8.8 Hz, 1H), 8.30 (br s, 1H), 7.85-7.74 (m, 2H), 7.56 (br d, J = 8.0 Hz, 1H), 7.30 (br t, J = 8.0 Hz, 1H), 5.79-5.67 (m, 1H), 5.59 (q, J = 6.8 Hz, 1H), 4.36-3.89 (m, 2H), 3.72 -3.45 (m, 2H), 3.17-3.06 (m, 3H), 3.01-2.91 (m, 1H), 2.87 (s, 3H), 2.70-2.61 (m, 3H), 2.61-2.37 (m, 1H) , 1.74 (br d, J = 6.8 Hz, 3H). LCMS [M+1] ⁺ : 445.2. 7-6

4-methyl- N -(( R )-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-7-((( S )-pyrrolidin-2-yl) Methoxy)

-1-amine ¹ H NMR (400 MHz, CD ₃ OD) δ = 7.97 (d, J = 9.2 Hz, 1H), 7.80 (d, J = 2.4 Hz, 1H), 7.71 (d, J = 8.0 Hz, 1H), 7.52 -7.46 (m, 2H), 7.23 (t, J = 7.6 Hz, 1H), 5.73 (q, J = 6.8 Hz, 1H), 4.28-4.22 (m, 1H), 4.13 (dd, J = 7.2, 9.2 Hz, 1H), 3.67-3.59 (m, 1H), 3.08-2.96 (m, 2H), 2.64 (s, 3H), 2.62 (s, 3H), 2.13-2.05 (m, 1H), 1.96-1.84 ( m, 2H), 1.73-1.66 (m, 1H), 1.63 (d, J = 7.2 Hz, 3H). LCMS [M+1] ⁺ : 445.2. 7-7

4-methyl- N -(( R )-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-7-((( R )-pyrrolidin-2-yl) Methoxy)

-1-amine hydrochloride ¹ H NMR (400 MHz, CD ₃ OD) δ = 8.40-8.38 (m, 2H), 7.91-7.78 (m, 2H), 7.55 (br d, J = 7.6 Hz, 1H), 7.30 (br t, J = 7.6 Hz, 1H), 5.60 (q, J = 7.2 Hz, 1H), 4.76 (dd, J = 3.2, 10.8 Hz, 1H), 4.70-4.59 (m, 1H), 4.23 (dq, J = 3.2, 8.0 Hz, 1H), 3.55-3.41 (m, 2H), 2.88 (s, 3H), 2.66 (s, 3H), 2.41 (dtd, J = 4.8, 7.6, 12.8 Hz, 1H), 2.33-2.11 (m , 2H), 2.11-2.00 (m, 1H), 1.75 (d, J = 6.8 Hz, 3H). LCMS [M+1] ⁺ : 445.2.

-1-胺

表8 實例 # 結構 光譜資料 8-2

(R )-7-乙基-4-甲基-N -(1-(5-(2-((甲基胺基)甲基)苯基)噻吩-2-基)乙基)呔

-1-胺 ¹ H NMR (400 MHz, CD₃ OD) δ 8.17 (s, 1H), 8.00 (d,J = 8.4 Hz, 1H), 7.80 (d,J = 8.4 Hz, 1H), 7.42 (d,J = 7.4 Hz, 1H), 7.37 - 7.25 (m, 3H), 7.09 (d,J = 3.5 Hz, 1H), 6.92 (d,J = 3.6 Hz, 1H), 5.90 (q,J = 7.0 Hz, 1H), 3.80 (s, 2H), 2.92 (q,J = 7.6 Hz, 2H), 2.25 (s, 3H), 1.81 (d,J = 6.9 Hz, 3H), 1.37 (t,J = 7.6 Hz, 3H)。LCMS [M+1]⁺ : 417.2 實例8-3

(R )-7-甲氧基-4-甲基-N -(1-(5-(2-((甲基胺基)甲基)苯基)噻吩-2-基)乙基)呔

-1-胺

Following the teaching of General Reaction Scheme IV and the procedure of Preparation Example 8-3 (below), the following compound of formula (I) as shown in Table 8, Example 8-1, and Example 8-2 as shown in Table 8 can be prepared: Example 8-1 ( R )-4,7-dimethyl- N -(1-(5-(2-((methylamino)methyl)phenyl)thiophen-2-yl)ethyl)

-1-amine

Table 8 Example # structure Spectral data 8-2

( R )-7-ethyl-4-methyl- N -(1-(5-(2-((methylamino)methyl)phenyl)thiophen-2-yl)ethyl)

-1-amine ¹ H NMR (400 MHz, CD ₃ OD) δ 8.17 (s, 1H), 8.00 (d, J = 8.4 Hz, 1H), 7.80 (d, J = 8.4 Hz, 1H), 7.42 (d, J = 7.4 Hz, 1H), 7.37-7.25 (m, 3H), 7.09 (d, J = 3.5 Hz, 1H), 6.92 (d, J = 3.6 Hz, 1H), 5.90 (q, J = 7.0 Hz, 1H), 3.80 (s, 2H), 2.92 (q, J = 7.6 Hz, 2H), 2.25 (s, 3H), 1.81 (d, J = 6.9 Hz, 3H), 1.37 (t, J = 7.6 Hz, 3H). LCMS [M+1] ⁺ : 417.2 Example 8-3

( R )-7-methoxy-4-methyl- N -(1-(5-(2-((methylamino)methyl)phenyl)thiophen-2-yl)ethyl)

-1-amine

烷（30.0 mL）中之溶液中添加Pd(PPh₃ )₂ Cl₂ （258 mg，367 µmol，0.03當量）。隨後將混合物在氮氣氛圍下在80℃下攪拌18小時。隨後將反應混合物倒入水（30.0 mL）中，且用乙酸乙酯（30.0 mL×2）萃取。將有機層用鹽水（30.0 mL）洗滌，經無水硫酸鈉乾燥且在真空下濃縮。該混合物無需進一步純化即可直接使用，得到呈褐色油狀之2-(1-乙氧基乙烯基)-5-甲氧基苯甲酸甲酯（2.80 g，11.9 mmol，96.8%產率，假定為100%純度）。LCMS [M+1]⁺ : 237.1。Step A: Add methyl 2-bromo-5-methoxybenzoate (3.00 g, 12.2 mmol, 1.00 equivalent) and tributyl(1-ethoxyvinyl)stannane (4.64 g, 12.9 mmol, 4.34 mL, 1.05 equivalent) in two

_{Add Pd(PPh 3} ) ₂ Cl ₂ (258 mg, 367 µmol, 0.03 equivalent) to the solution in alkane (30.0 mL). The mixture was then stirred at 80°C for 18 hours under a nitrogen atmosphere. The reaction mixture was then poured into water (30.0 mL), and extracted with ethyl acetate (30.0 mL×2). The organic layer was washed with brine (30.0 mL), dried over anhydrous sodium sulfate and concentrated under vacuum. The mixture can be used directly without further purification to obtain methyl 2-(1-ethoxyvinyl)-5-methoxybenzoate (2.80 g, 11.9 mmol, 96.8% yield, assuming that 100% purity). LCMS [M+1] ⁺ : 237.1.

Step B: Combine methyl 2-(1-ethoxyvinyl)-5-methoxybenzoate (2.50 g, 10.6 mmol, 1.00 equivalent) and 10% aqueous hydrogen chloride solution (386 mg, 10.6 mmol, 378 µL, 1.00 equivalent) in THF (20.0 mL) was stirred at 20°C for 1 hour. The reaction mixture was then poured into water (20.0 mL), and extracted with ethyl acetate (25.0 mL×3). The organic layer was washed with brine (50.0 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum to give a residue. The residue was purified by flash silica gel chromatography ( 0-20% ethyl acetate/petroleum ether) to obtain methyl 2-acetyl-5-methoxybenzoate (1.40 g, 5.72) as a yellow oil mmol, 54.1% yield, 85.1% purity). LCMS [M+1] ⁺ : 209.0.

¹ H NMR (400 MHz, CD ₃ OD) δ = 2.51 (s, 3 H) 3.86 (d, J = 10.0 Hz, 6 H) 7.06-7.15 (m, 2 H) 7.70-7.79 (m, 1 H) .

-1(2H )-酮（1.10 g，5.74 mmol，91.9%產率，99.3%純度）。LCMS [M+1]⁺ : 191.0。Step C: Add hydrazine hydrate (938 mg, 18.7 mmol, 910 µL, 98% purity, 3.00 equivalent). The mixture was then stirred at 80°C for 1 hour under a nitrogen atmosphere. The reaction mixture was then poured into water (20.0 mL), and extracted with ethyl acetate (30.0 mL×2). The organic layer was washed with brine (30.0 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum to give a residue. The crude product can be used in the next step without purification to obtain 7-methoxy-4-methyl group as a white solid.

-1( 2H )-ketone (1.10 g, 5.74 mmol, 91.9% yield, 99.3% purity). LCMS [M+1] ⁺ : 191.0.

-1(2H )-酮（0.90 g，4.73 mmol，1.00當量）及三氯氧磷（15.2 g，99.4 mmol，9.23 mL，21.0當量）之混合物在115℃下攪拌18小時。隨後將混合物倒入水（25.0 mL）中。添加飽和碳酸鈉溶液直至pH=9。用乙酸乙酯（2×25.0 mL）萃取混合物。將合併之有機相用鹽水（飽和，20.0 mL）洗滌，經硫酸鈉乾燥，過濾，且在減壓下蒸發溶劑。將殘餘物藉由製備型TLC（SiO₂ ，二氯甲烷:甲醇＝10:1）之管柱層析法純化，得到呈白色固體狀之4-氯-6-甲氧基-1-甲基呔

（240 mg，1.14 mmol，24.0%產率，98.8%純度）。LCMS [M+1]⁺ : 209.0。Step D: Add 7-methoxy-4-methyl

A mixture of -1( 2H )-ketone (0.90 g, 4.73 mmol, 1.00 equivalent) and phosphorus oxychloride (15.2 g, 99.4 mmol, 9.23 mL, 21.0 equivalent) was stirred at 115°C for 18 hours. The mixture was then poured into water (25.0 mL). Add saturated sodium carbonate solution until pH=9. The mixture was extracted with ethyl acetate (2×25.0 mL). The combined organic phase was washed with brine (saturated, 20.0 mL), dried over sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The residue was purified by preparative TLC (SiO ₂ , dichloromethane: methanol = 10:1) column chromatography to obtain 4-chloro-6-methoxy-1-methyl as a white solid Hum

(240 mg, 1.14 mmol, 24.0% yield, 98.8% purity). LCMS [M+1] ⁺ : 209.0.

（30.0 mg，144 µmol，1.00當量）及氟化銫（66.0 mg，435 µmol，16.0 µL，3.02當量）於二甲基亞碸（1.00 mL）中之混合物在130℃下攪拌18小時。隨後將混合物冷卻至25℃，用乙酸乙酯（5.00 mL）稀釋，用鹽水（3.00×5 mL）洗滌，經硫酸鈉乾燥，過濾，且在減壓下蒸發溶劑，得到殘餘物。將殘餘物藉由製備型HPLC（管柱：Boston Green ODS 150×30 mm×5 um；移動相：A相：[水（0.1% TFA）]，B相：乙腈；B%：38%-68%）純化，得到呈白色固體狀之(R )-(2-(5-(1-((7-甲氧基-4-甲基呔

-1-基)胺基)乙基)噻吩-2-基)苯甲基)(甲基)胺甲酸第三丁酯（10.0 mg，18.7 µmol，13.0%產率，96.8%純度）。LCMS [M+1]⁺ : 519.2。Step E: Add ( R )-(2-(5-(1-aminoethyl)thiophen-2-yl)benzyl)(methyl)carbamic acid tert-butyl ester (49.3 mg, 142 µmol, 0.99 Equivalent), 4-chloro-6-methoxy-1-methyl

A mixture of (30.0 mg, 144 µmol, 1.00 equivalent) and cesium fluoride (66.0 mg, 435 µmol, 16.0 µL, 3.02 equivalent) in dimethyl sulfoxide (1.00 mL) was stirred at 130°C for 18 hours. The mixture was then cooled to 25°C, diluted with ethyl acetate (5.00 mL), washed with brine (3.00×5 mL), dried over sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to give a residue. The residue was subjected to preparative HPLC (column: Boston Green ODS 150×30 mm×5 um; mobile phase: phase A: [water (0.1% TFA)], phase B: acetonitrile; B%: 38%-68 %) Purification to obtain ( R )-(2-(5-(1-((7-methoxy-4-methyl 呔) as a white solid

-1-yl)amino)ethyl)thiophen-2-yl)benzyl)(methyl)tert-butyl carbamate (10.0 mg, 18.7 µmol, 13.0% yield, 96.8% purity). LCMS [M+1] ⁺ : 519.2.

-1-基)胺基)乙基)噻吩-2-基)苯甲基)(甲基)胺甲酸第三丁酯（8.00 mg，15.4 µmol，1.00當量）及2,6-二甲吡啶（16.5 mg，154 µmol，18.0 µL，10.0當量）於二氯甲烷（2.00 mL）中之混合物中添加TMSOTf（24.0 mg，108 µmol，19.5 µL，7.00當量），隨後將其在氮氣氛圍下在20℃下攪拌2小時。向混合物中添加N,N- 二異丙基乙胺（0.10 ml），且將混合物在減壓下濃縮，得到殘餘物。將殘餘物藉由製備型HPLC（管柱：Aegla DuraShell C18 150×25 mm×5 um；移動相：A相：[水（0.05% NH₃ H₂ O+10mM NH₄ HCO₃ ）]，相B：乙腈；B%：38%-68%）純化，得到呈白色固體狀之(R )-7-甲氧基-4-甲基-N -(1-(5-(2-((甲基胺基)甲基)苯基)噻吩-2-基)乙基)呔

-1-胺（3.00 mg，7.10 µmol，46.0%產率，99.0%純度）。LCMS [M+1]⁺ : 419.2。Step F: To ( R )-(2-(5-(1-((7-methoxy-4-methyl

-1-yl)amino)ethyl)thiophen-2-yl)benzyl)(methyl)carbamate (8.00 mg, 15.4 µmol, 1.00 equivalent) and 2,6-lutidine ( 16.5 mg, 154 µmol, 18.0 µL, 10.0 equivalent) was added to the mixture in dichloromethane (2.00 mL) with TMSOTf (24.0 mg, 108 µmol, 19.5 µL, 7.00 equivalent), and then placed at 20°C under a nitrogen atmosphere Stir for 2 hours. To the mixture was added N,N -diisopropylethylamine (0.10 ml), and the mixture was concentrated under reduced pressure to obtain a residue. The residue was subjected to preparative HPLC (column: Aegla DuraShell C18 150×25 mm×5 um; mobile phase: phase A: [water (0.05% NH ₃ H ₂ O+10 mM NH ₄ HCO ₃ )], phase B : Acetonitrile; B%: 38%-68%) to obtain ( R )-7-methoxy-4-methyl- N -(1-(5-(2-((methyl (Amino) methyl) phenyl) thiophen-2-yl) ethyl) 呔

-1-amine (3.00 mg, 7.10 µmol, 46.0% yield, 99.0% purity). LCMS [M+1] ⁺ : 419.2.

-1-基)呔

-1-胺

¹ H NMR (500 MHz, CD ₃ OD) δ = 8.01 (d, J = 9.0 Hz, 1H), 7.73 (d, J = 2.5 Hz, 1H), 7.49 (dd, J = 9.0, 2.5 Hz, 1H) , 7.44 (d, J = 6.5 Hz, 1H), 7.33-7.37 (m, 2H), 7.26-7.34 (m, 1H), 7.10 (d, J = 3.0 Hz, 1H), 6.93 (d, J = 3.5 Hz, 1H), 5.85-5.96 (m, 1H), 4.02 (s, 3H), 3.86 (s, 2H), 2.73 (s, 3H), 2.29 (s, 3H), 1.82 (d, J = 7.0 Hz , 3H). Example 9-1 ( R )-4-methoxy- N -(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-7-(piper

-1-base) 呔

-1-amine

-1,4-二酮（3.00 g，12.4 mmol，1.00當量）於三氯氧磷（40.0 mL）中之溶液中逐滴添加N,N- 二異丙基乙胺（4.02 g，31.1 mmol，5.42 mL，2.50當量）。隨後將反應在120℃下攪拌12小時。將混合物冷卻至25℃且真空濃縮，以移除大部分三氯氧磷且得到殘餘物。將殘餘物倒入冰水（100 mL）中，將所得水溶液用飽和碳酸氫鈉水溶液調節至pH＝7，隨後用二氯甲烷（50.0 mL×2）萃取。將合併之有機相用鹽水（30.0 mL×2）洗滌，經無水硫酸鈉乾燥，過濾，且在真空下濃縮，得到呈黃色固體狀之6-溴-1,4-二氯呔

（1.20 g，4.32 mmol，粗製），其無需進一步純化。LCMS [M+3]⁺ : 279.0。Step A: At 25℃, add 6-bromo-2,3-dihydrogen

-1,4-Dione (3.00 g, 12.4 mmol, 1.00 equivalent) in phosphorus oxychloride (40.0 mL) was added dropwise N,N -diisopropylethylamine (4.02 g, 31.1 mmol, 5.42 mL, 2.50 equivalent). The reaction was then stirred at 120°C for 12 hours. The mixture was cooled to 25°C and concentrated in vacuo to remove most of the phosphorus oxychloride and obtain a residue. The residue was poured into ice water (100 mL), the resulting aqueous solution was adjusted to pH=7 with saturated aqueous sodium bicarbonate solution, and then extracted with dichloromethane (50.0 mL×2). The combined organic phase was washed with brine (30.0 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain 6-bromo-1,4-dichlorobenzene as a yellow solid

(1.20 g, 4.32 mmol, crude), which requires no further purification. LCMS [M+3] ⁺ : 279.0.

（500 mg，1.80 mmol，1.00當量）及(R )-1-(2-甲基-3-(三氟甲基)苯基)乙-1-胺（365 mg，1.80 mmol，1.00當量）於DMSO（10.0 mL）中之混合物中添加氟化鉀（313 mg，5.40 mmol，126 µL，3.00當量）、N,N- 二異丙基乙胺（465 mg，3.60 mmol，627 µL，2.00當量）。隨後將反應混合物在130℃下攪拌3小時。在此之後，將反應冷卻至25℃，用乙酸乙酯（20.0 mL）稀釋，用鹽水（5.00 mL×2）洗滌，經無水硫酸鈉乾燥，過濾，且在真空下濃縮，得到殘餘物。將殘餘物藉由製備型TLC（石油醚/乙酸乙酯＝3/1）純化，得到呈白色固體狀之(R )-7-溴-4-氯-N -(1-(2-甲基-3-(三氟甲基)苯基)乙基)呔

-1-胺（360 mg，769 µmol，42.7%產率）。LCMS [M+3]⁺ : 446.1。Step B: Under nitrogen atmosphere, add 6-bromo-1,4-dichloro

(500 mg, 1.80 mmol, 1.00 equivalent) and ( R )-1-(2-methyl-3-(trifluoromethyl)phenyl)ethan-1-amine (365 mg, 1.80 mmol, 1.00 equivalent) in Add potassium fluoride (313 mg, 5.40 mmol, 126 µL, 3.00 equivalents) and N,N -diisopropylethylamine (465 mg, 3.60 mmol, 627 µL, 2.00 equivalents) to the mixture in DMSO (10.0 mL) . The reaction mixture was then stirred at 130°C for 3 hours. After this, the reaction was cooled to 25°C, diluted with ethyl acetate (20.0 mL), washed with brine (5.00 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain a residue. The residue was purified by preparative TLC (petroleum ether/ethyl acetate = 3/1) to obtain ( R )-7-bromo-4-chloro- N -(1-(2-methyl) as a white solid -3-(trifluoromethyl)phenyl)ethyl)

-1-amine (360 mg, 769 µmol, 42.7% yield). LCMS [M+3] ⁺ : 446.1.

¹ H NMR (400 MHz, CDCl ₃ ) δ = 8.15-8.01 (m, 2H), 7.99-7.79 (m, 1H), 7.63 (d, J = 8.0 Hz, 1H), 7.56-7.50 (m, 1H) , 7.23 (s, 1H), 5.91-5.77 (m, 1H), 5.45 (br d, J = 6.4 Hz, 1H), 2.55 (s, 3H), 1.65 (d, J = 6.8 Hz, 3H).

-1-胺（330 mg，742 µmol，1.00當量）於甲醇（5.00 mL）中之混合物中添加甲醇鈉（200 mg，3.71 mmol，5.00當量）。將反應混合物在微波反應器中在110℃下攪拌2小時。隨後將反應混合物冷卻至25℃，且在減壓下濃縮，得到殘餘物。將殘餘物藉由管柱層析法（SiO₂ ，石油醚/乙酸乙酯＝50/1至1/1）純化，得到呈白色固體狀之(R )-7-溴-4-甲氧基-N -(1-(2-甲基-3-(三氟甲基)苯基)乙基)呔

-1-胺（281 mg，638 µmol，86.0%產率）。Step C: Under nitrogen, add ( R )-7-bromo-4-chloro- N -(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)

To a mixture of -1-amine (330 mg, 742 µmol, 1.00 equivalent) in methanol (5.00 mL) was added sodium methoxide (200 mg, 3.71 mmol, 5.00 equivalent). The reaction mixture was stirred in a microwave reactor at 110°C for 2 hours. The reaction mixture was then cooled to 25°C and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 50/1 to 1/1) to obtain ( R )-7-bromo-4-methoxy as a white solid -N -(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)

-1-amine (281 mg, 638 µmol, 86.0% yield).

-1-胺（240 mg，545 µmol，4.00當量）及哌

-1-羧酸第三丁酯（25.4 mg，136 µmol，1.00當量）於二

烷（5.00 mL）中之溶液中一次添加RuPhos Pd G3（5.70 mg，6.81 µmol，0.05當量）及碳酸銫（178 mg，545 µmol，4.00當量）。將混合物在110℃下攪拌3小時。LCMS顯示反應完成。將懸浮液藉由矽藻土墊過濾，且將濾餅用乙酸乙酯（30.0 mL）洗滌。將合併之濾液濃縮，得到殘餘物。將殘餘物藉由製備型HPLC（管柱：Phenomenex Synergi C18 150×30 mm×4 um，移動相A：水（0.1% TFA），移動相B：乙腈。梯度：49%〜69% B）純化，得到呈白色固體狀之(R )-4-(1-甲氧基-4-((1-(2-甲基-3-(三氟甲基)苯基)乙基)胺基)呔

-6-基)哌

-1-羧酸第三丁酯（70.0 mg，128 µmol，94.1%產率）。LCMS [M+1]⁺ : 546.3。Step D: Under a nitrogen atmosphere at 20°C, to ( R )-7-bromo-4-methoxy- N -(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl Base) eh

-1-amine (240 mg, 545 µmol, 4.00 equivalents) and piper

-1- tert-butyl carboxylate (25.4 mg, 136 µmol, 1.00 equivalent) in two

Add RuPhos Pd G3 (5.70 mg, 6.81 µmol, 0.05 equivalent) and cesium carbonate (178 mg, 545 µmol, 4.00 equivalent) to a solution in alkane (5.00 mL) at once. The mixture was stirred at 110°C for 3 hours. LCMS showed that the reaction was complete. The suspension was filtered through a pad of celite, and the filter cake was washed with ethyl acetate (30.0 mL). The combined filtrates were concentrated to obtain a residue. The residue was purified by preparative HPLC (column: Phenomenex Synergi C18 150×30 mm×4 um, mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile. Gradient: 49%~69% B) To obtain (R )-4-(1-methoxy-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino) in the form of a white solid

-6-yl)piperidine

Tert-butyl-1-carboxylate (70.0 mg, 128 µmol, 94.1% yield). LCMS [M+1] ⁺ : 546.3.

-6-基)哌

-1-羧酸第三丁酯（50.0 mg，91.6 µmol，1.00當量）於二氯甲烷（1.00 mL）中之混合物中添加三氟乙酸（0.20 mL）。將混合物在20℃下攪拌1小時。LCMS顯示反應完成。將混合物在減壓下濃縮，得到殘餘物。將殘餘物藉由製備型HPLC（管柱：Phenomenex Synergi C18 100×21.2 mm×4 um，使用TFA水及乙腈作為溶離劑。移動相A：水（0.1% TFA），移動相B：乙腈。梯度：14%〜44%B）純化，得到呈白色固體狀之(R )-4-甲氧基-N -(1-(2-甲基-3-(三氟甲基)苯基)乙基)-7-(哌

-1-基)呔

-1-胺（35.0 mg，78.6 µmol，85.7%產率）。LCMS [M+1]⁺ : 446.2。Step E: To ( R )-4-(1-methoxy-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)

-6-yl)piperidine

To a mixture of tert-butyl-1-carboxylate (50.0 mg, 91.6 µmol, 1.00 equivalent) in dichloromethane (1.00 mL) was added trifluoroacetic acid (0.20 mL). The mixture was stirred at 20°C for 1 hour. LCMS showed that the reaction was complete. The mixture was concentrated under reduced pressure to obtain a residue. The residue was subjected to preparative HPLC (column: Phenomenex Synergi C18 100×21.2 mm×4 um, using TFA water and acetonitrile as eluents. Mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile. Gradient. ：14%～44% B) Purify to obtain ( R )-4-methoxy- N -(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl as a white solid )-7-(Piper

-1-base) 呔

-1-amine (35.0 mg, 78.6 µmol, 85.7% yield). LCMS [M+1] ⁺ : 446.2.

¹ H NMR (400 MHz, CD ₃ OD) δ = 8.18 (d, J = 9.2 Hz, 1H), 8.06 (d, J = 2.8 Hz, 1H), 7.82 (dd, J = 2.4, 9.2 Hz, 1H) , 7.64-7.77 (m, 2H), 7.36-7.46 (m, 1H), 5.42 (q, J = 6.4 Hz, 1H), 4.07 (s, 3H), 3.75-3.86 (m, 4H), 3.38-3.47 (m, 4H), 2.51 (s, 3H), 1.80 (d, J = 6.8 Hz, 3H).

(R )-N ¹ ,N ¹ -二甲基-N ⁴ -(1-(2-甲基-3-(三氟甲基)苯基)乙基)-6-(哌

-1-基)呔

-1,4-二胺 ¹ H NMR (500 MHz, CD₃ OD) δ = 8.26 (d,J = 9.0 Hz, 1H), 7.81 (br s, 1H), 7.67 (br d,J = 7.5 Hz, 2H), 7.52 (br d,J = 8.0 Hz, 1H), 7.17-7.32 (m, 1H), 5.43 (q,J = 7.5 Hz, 1H), 3.92 (br s, 4H), 3.44-3.48 (m, 4H), 3.23 (br s, 6H), 2.58 (s, 3H), 1.63 (br d,J = 7.0 Hz, 3H)。LCMS [M+1]⁺ : 459.2 實例10-1 (R )-4-甲基-N -(1-(2-甲基-3-(三氟甲基)苯基)乙基)-7-(哌啶-4-基)呔

-1-胺

Following the teaching of General Reaction Scheme III and the method of preparing Example 9-1, the following compounds of formula (I) as shown in Table 9 were prepared, Example 9-2: Table 9 Example # structure Spectral data 9-2

( R ) -N ¹ , N ¹ -Dimethyl- N ⁴ -(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-6-(piper

-1-base) 呔

-1,4-diamine ¹ H NMR (500 MHz, CD ₃ OD) δ = 8.26 (d, J = 9.0 Hz, 1H), 7.81 (br s, 1H), 7.67 (br d, J = 7.5 Hz, 2H), 7.52 (br d , J = 8.0 Hz, 1H), 7.17-7.32 (m, 1H), 5.43 (q, J = 7.5 Hz, 1H), 3.92 (br s, 4H), 3.44-3.48 (m, 4H), 3.23 (br s, 6H), 2.58 (s, 3H), 1.63 (br d, J = 7.0 Hz, 3H). LCMS [M+1] ⁺ : 459.2 Example 10-1 ( R )-4-methyl- N- (1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-7-(piperidin-4-yl)

-1-amine

-1(2H )-酮（4 g，16.73 mmol，1.00當量）於POCl₃ （75.54 g，492.66 mmol，45.78 mL，29.44當量）中之混合物在N₂ 氛圍下在20℃下攪拌，隨後加熱至100℃且攪拌5小時。將混合物冷卻至20℃，且在減壓下濃縮。將殘餘物緩慢倒入水中，且用飽和NaHCO₃ 中和直至pH=8。隨後將乙酸乙酯（100 mL）添加至混合物中，且在25℃下攪拌30分鐘。過濾混合物，且收集濾餅。將殘餘物使用矽膠管柱(0-55%石油醚/EtOAc）純化，得到呈黃色固體狀之6-溴-4-氯-1-甲基呔

（2.2 g，8.54 mmol，51.06%產率）。Step A: Add 7-bromo-4-methyl

A mixture of -1(2 H )-ketone (4 g, 16.73 mmol, 1.00 equivalent) in POCl ₃ (75.54 g, 492.66 mmol, 45.78 mL, 29.44 equivalent) was stirred at 20°C under _{N 2 atmosphere, and then heated} Bring to 100°C and stir for 5 hours. The mixture was cooled to 20°C and concentrated under reduced pressure. The residue was slowly poured into water and _{neutralized with saturated NaHCO 3} until pH=8. Then ethyl acetate (100 mL) was added to the mixture, and stirred at 25°C for 30 minutes. The mixture was filtered, and the filter cake was collected. The residue was purified using a silica gel column (0-55% petroleum ether/EtOAc) to obtain 6-bromo-4-chloro-1-methyl as a yellow solid

(2.2 g, 8.54 mmol, 51.06% yield).

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.41 (d, J = 1.5 Hz, 1H), 8.29-8.34 (m, 1H), 8.24-8.28 (m, 1H), 2.89-2.93 (m, 3H ).

（0.6 g，2.32 mmol，1.00當量）及(R )-1-(2-甲基-3-(三氟甲基)苯基)乙-1-胺（472 mg，2.32 mmol，1.00當量）於DMSO（4 mL）中之混合物中一次添加N,N- 二異丙基乙胺（602 mg，2.33 mmol，810 µL，2.00當量）及CsF（706 mg，4.66 mmol，2.00當量）。將混合物在130℃下攪拌3小時。在此時間後，將反應冷卻至室溫，將水（50 mL）添加至反應混合物中，且用乙酸乙酯（3×30 mL）萃取。將合併之有機層用鹽水（飽和，20 mL）洗滌，經Na₂ SO₄ 乾燥，過濾且濃縮，得到殘餘物。將殘餘物使用製備型TLC板純化，用50%乙酸乙酯/石油醚洗脫，得到呈黃色油狀之(R )-7-溴-4-甲基-N -(1-(2-甲基-3-(三氟甲基)苯基)乙基)呔

-1-胺（0.6 g，1414 µmol，60.70%產率）。Step B: Under N ₂ atmosphere at 20 ℃, to 6-bromo-4-chloro-1-methyl

(0.6 g, 2.32 mmol, 1.00 equivalent) and ( R )-1-(2-methyl-3-(trifluoromethyl)phenyl)ethan-1-amine (472 mg, 2.32 mmol, 1.00 equivalent) in Add N,N -diisopropylethylamine (602 mg, 2.33 mmol, 810 µL, 2.00 equivalent) and CsF (706 mg, 4.66 mmol, 2.00 equivalent) to the mixture in DMSO (4 mL) at once. The mixture was stirred at 130°C for 3 hours. After this time, the reaction was cooled to room temperature, water (50 mL) was added to the reaction mixture, and it was extracted with ethyl acetate (3×30 mL). The combined organic layers were washed with brine (saturated, 20 mL), dried over Na ₂ SO _4, filtered and concentrated to give a residue. The residue was purified using a preparative TLC plate and eluted with 50% ethyl acetate/petroleum ether to give ( R )-7-bromo-4-methyl- N -(1-(2-methyl) as a yellow oil 3-(trifluoromethyl)phenyl)ethyl)

-1-amine (0.6 g, 1414 µmol, 60.70% yield).

Note: The reaction needs to be set up in _{a glove box under N 2} atmosphere to avoid moisture. All reagents including solvent (DMSO) must be dried.

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.97 (s, 1H), 7.87-7.93 (m, 1H), 7.79-7.85 (m, 1H), 7.66 (d, J = 7.6 Hz, 1H), 7.54 ( d, J = 7.6 Hz, 1H), 7.26-7.29 (m, 1H), 5.88 (quint, J = 6.4 Hz, 1H), 5.12 (br s, 1H), 2.78 (s, 3H), 2.57 (s, 3H), 1.66 (d, J = 6.8 Hz, 3H).

-1-胺（35.0 mg，82.5 µmol，1.00當量）及4-(4,4,5,5-四甲基-1,3,2-二氧雜環戊硼烷-2-基)-3,6-二氫吡啶-1(2H )-羧酸第三丁酯（38.3 mg，124 µmol，1.50當量）於四氫呋喃（3.00 mL）及水（0.60 mL）中之混合物中一次添加碳酸鈉（26.2 mg，247 µmol，3.00當量）及Pd(dppf)Cl₂ （6.04 mg，8.25 µmol，0.10當量）。將混合物在80℃下攪拌2小時，隨後冷卻至室溫，且將混合物用乙酸乙酯（30.0 mL）稀釋，用水（10.0 mL×3）洗滌。將合併之有機層用鹽水（20.0 mL）洗滌，經硫酸鈉乾燥且過濾。濃縮濾液，得到呈黃色油狀之粗產物。將黃色油藉由製備型TLC（SiO₂ ，石油醚/乙酸乙酯＝2/1）純化，得到呈黃色油狀之(R )-4-(1-甲基-4-((1-(2-甲基-3-(三氟甲基)苯基)乙基)胺基)呔

-6-基)-3,6-二氫吡啶-1(2H )-羧酸第三丁酯（32.0 mg，60.8 µmol，73.7%產率）。LCMS [M+1]⁺ : 527.3。Step C: Add ( R )-7-bromo-4-methyl- N -(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl to (R )-7-bromo-4-methyl-N -(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl ) Eh

-1-amine (35.0 mg, 82.5 µmol, 1.00 equivalent) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3 ,6-Dihydropyridine-1(2 H )-tert-butyl carboxylate (38.3 mg, 124 µmol, 1.50 equivalents) in a mixture of tetrahydrofuran (3.00 mL) and water (0.60 mL) was added sodium carbonate ( 26.2 mg, 247 µmol, 3.00 equivalents) and Pd(dppf)Cl ₂ (6.04 mg, 8.25 µmol, 0.10 equivalents). The mixture was stirred at 80°C for 2 hours, then cooled to room temperature, and the mixture was diluted with ethyl acetate (30.0 mL) and washed with water (10.0 mL×3). The combined organic layer was washed with brine (20.0 mL), dried over sodium sulfate and filtered. The filtrate was concentrated to obtain the crude product in the form of a yellow oil. The yellow oil was purified by preparative TLC (SiO ₂ , petroleum ether/ethyl acetate = 2/1) to obtain ( R )-4-(1-methyl-4-((1-( 2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)

-6-yl)-3,6-dihydropyridine-1(2 H )-tert-butyl carboxylate (32.0 mg, 60.8 µmol, 73.7% yield). LCMS [M+1] ⁺ : 527.3.

-6-基)-3,6-二氫吡啶-1(2H )-羧酸第三丁酯（14.0 mg，26.6 µmol，1.00當量）於甲醇（3.00 mL）中之溶液中添加Pd/C（3.62 mg，3.41 µmol，10%純度，0.13當量）。將懸浮液在真空下脫氣且用氫氣沖洗若干次。將混合物在氫氣（15.0 psi）下在25℃下攪拌2小時，隨後通過矽藻土墊過濾，且將濾餅用乙酸乙酯（30.0 mL）洗滌。將合併之濾液濃縮，得到呈黃色油狀之(R )-4-(1-甲基-4-((1-(2-甲基-3-(三氟甲基)苯基)乙基)胺基)呔

-6-基)哌啶-1-羧酸第三丁酯（14.0 mg，26.5 µmol，99.6%產率）。該粗產物無需進一步純化即可直接用於下一步。LCMS [M+1]⁺ : 529.3。Step D: Under nitrogen atmosphere, to ( R )-4-(1-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino) Hum

-6-yl)-3,6-dihydropyridine-1(2 H )-tert-butyl carboxylate (14.0 mg, 26.6 µmol, 1.00 equivalent) in methanol (3.00 mL), add Pd/C (3.62 mg, 3.41 µmol, 10% purity, 0.13 equivalent). The suspension was degassed under vacuum and flushed with hydrogen several times. The mixture was stirred under hydrogen (15.0 psi) at 25°C for 2 hours, then filtered through a pad of Celite, and the filter cake was washed with ethyl acetate (30.0 mL). The combined filtrates were concentrated to give ( R )-4-(1-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl) as a yellow oil Amino)

-6-yl)piperidine-1-carboxylic acid tert-butyl ester (14.0 mg, 26.5 µmol, 99.6% yield). The crude product can be used directly in the next step without further purification. LCMS [M+1] ⁺ : 529.3.

-6-基)哌啶-1-羧酸第三丁酯（14 mg，26.5 µmol，1.00當量）於二氯甲烷（2.00 mL）及三氟乙酸（0.40 mL）中之混合物在20℃下攪拌2小時，隨後濃縮，得到殘餘物。將殘餘物藉由製備型HPLC（管柱：Phenomenex Synergi C18 150×30 mm×4 um，使用TFA水及乙腈作為溶離劑。移動相A：水（0.1% TFA），移動相B：乙腈。梯度：20%-50% B）純化，得到呈黃色固體狀之(R )-4-甲基-N -(1-(2-甲基-3-(三氟甲基)苯基)乙基)-7-(哌啶-4-基)呔

-1-胺（9.00 mg，21.0 µmol，79.3%產率）。LCMS [M+1]⁺ : 429.1。Step E: Add ( R )-4-(1-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)

A mixture of -6-yl)piperidine-1-carboxylic acid tert-butyl ester (14 mg, 26.5 µmol, 1.00 equivalent) in dichloromethane (2.00 mL) and trifluoroacetic acid (0.40 mL) was stirred at 20°C 2 hours, followed by concentration to obtain a residue. The residue was subjected to preparative HPLC (column: Phenomenex Synergi C18 150×30 mm×4 um, using TFA water and acetonitrile as eluents. Mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile. Gradient. : 20%-50% B) Purify to obtain ( R )-4-methyl- N -(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl) as a yellow solid -7-(piperidin-4-yl)

-1-amine (9.00 mg, 21.0 µmol, 79.3% yield). LCMS [M+1] ⁺ : 429.1.

啉基-4-(三氟甲基)呔

-1-胺

¹ H NMR (400 MHz, CD ₃ OD) δ = 8.67 (s, 1H), 8.37 (d, J = 8.8 Hz, 1H), 8.12 (d, J = 8.4 Hz, 1H), 7.73 (d, J = 8.4 Hz, 1H), 7.55 (d, J = 8.0 Hz, 1H), 7.29 (t, J = 7.6 Hz, 1H), 5.57 (q, J = 6.8 Hz, 1H), 3.61 (br d, J = 12.8 Hz, 2H), 3.20-3.30 (m, 3H), 2.87 (s, 3H), 2.63 (s, 3H), 2.21-2.32 (m, 2H), 2.05-2.20 (m, 2H), 1.71 (d, J = 6.8 Hz, 3H). Example 10-2 ( R ) -N -(1-(5-(2-((methylamino)methyl)phenyl)thiophen-2-yl)ethyl)-7-

Linyl-4-(trifluoromethyl)

-1-amine

Step A: Add CsF (223 mg, 1.46) to a solution of dimethyl 4-bromophthalate (2.00 g, 7.32 mmol, 1.00 equivalent) in 1,2-dimethoxyethane (25.0 mL) mmol, 54.0 µL, 0.20 equivalent) and TMSCF ₃ (1.25 g, 8.79 mmol, 1.20 equivalent). The mixture was stirred between 0-25°C for 1 hour. The mixture was then partitioned between ethyl acetate (1.00 mL) and water (15.0 mL). The organic phase was separated, washed with brine (15.0 mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 6-bromo-3-methoxy-3-(trifluoro Methyl)isobenzofuran-1(3 H )-one and 5-bromo-3-methoxy-3-(trifluoromethyl)isobenzofuran-1(3 H )-one mixture (2.20 g, crude).

-1(2H )-酮（680 mg，2.32 mmol，32.8%產率）。Step B: Add 6-bromo-3-methoxy-3-(trifluoromethyl)isobenzofuran-1(3 H )-one and 5-bromo-3-methoxy-3-(trifluoromethyl) Methyl)isobenzofuran-1(3 H )-one (2.20 g, 7.07 mmol, 1.00 equivalent) in THF (25.0mL) was added with hydrazine hydrate (708 mg, 14.6 mmol, 688 µL, 2.00 equivalent) ). The mixture was stirred at 75°C for 18 hours, and then concentrated under reduced pressure to remove the solvent. The residue was purified by flash silica gel chromatography (SiO ₂ , petroleum ether/ethyl acetate = 10/1 to 8/1) to obtain 7-bromo-4-(trifluoromethyl) as a white solid

-1( 2H )-ketone (680 mg, 2.32 mmol, 32.8% yield).

¹ H NMR (400 MHz, CD ₃ OD) δ = 8.54 (d, J = 1.71 Hz, 1H), 8.15 (dd, J = 8.68, 2.08 Hz, 1H), 7.91 (dd, J = 8.80, 1.47 Hz, 1H).

-1(2H )-酮（200 mg，683 µmol，1.00當量）於POCl₃ （3.30 g，21.5 mmol，2.00 mL，31.5當量）中之溶液中添加吡啶（108 mg，1.37 mmol，110 µL，2.00當量）。將混合物在105℃下攪拌1.5小時，隨後在減壓下濃縮，得到呈白色固體狀之6-溴-4-氯-1-(三氟甲基)呔

（210 mg，粗製）。Step C: Add 7-bromo-4-(trifluoromethyl) to 7-bromo-4-(trifluoromethyl) at 20°C

-1(2 H )-ketone (200 mg, 683 µmol, 1.00 equivalent) in POCl ₃ (3.30 g, 21.5 mmol, 2.00 mL, 31.5 equivalent) was added with pyridine (108 mg, 1.37 mmol, 110 µL, 2.00 equivalent). The mixture was stirred at 105°C for 1.5 hours, and then concentrated under reduced pressure to obtain 6-bromo-4-chloro-1-(trifluoromethyl) as a white solid.

(210 mg, crude).

（135 mg，433 µmol，1.50當量）於DMSO（2.00 mL）中之溶液中添加N,N- 二異丙基乙胺（112 mg，866 µmol，151 µL，3.00當量）、KF（1.68 mg，28.8 µmol，6.76 µL，0.10當量）及(R )-(2-(5-(1-胺基乙基)噻吩-2-基)苯甲基)(甲基)胺甲酸第三丁酯（0.10 g，289 µmol，100當量）。將混合物在130℃下在微波中攪拌45分鐘。將混合物用水（2.00 mL）稀釋，且用乙酸乙酯（2.00 mL×3）萃取。將合併之有機層用水（2.00 mL×2）洗滌，經無水硫酸鈉乾燥，過濾且在減壓下濃縮，得到殘餘物。將殘餘物藉由製備型TLC（SiO₂ ，石油醚:乙酸乙酯＝5:1）純化，得到呈黃色油狀之(R )-(2-(5-(1-((7-溴-4-(三氟甲基)呔

-1-基)胺基)乙基)噻吩-2-基)苯甲基)(甲基)胺甲酸第三丁酯（46.0 mg，74.0 µmol，25.6%產率）。Step D: Add 6-bromo-4-chloro-1-(trifluoromethyl)

(135 mg, 433 µmol, 1.50 equivalents) was added to a solution in DMSO (2.00 mL) with N,N -diisopropylethylamine (112 mg, 866 µmol, 151 µL, 3.00 equivalents), KF (1.68 mg, 28.8 µmol, 6.76 µL, 0.10 equivalent) and ( R )-(2-(5-(1-aminoethyl)thiophen-2-yl)benzyl)(methyl)carbamic acid tert-butyl ester (0.10 g, 289 µmol, 100 equivalents). The mixture was stirred in the microwave at 130°C for 45 minutes. The mixture was diluted with water (2.00 mL), and extracted with ethyl acetate (2.00 mL×3). The combined organic layer was washed with water (2.00 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by preparative TLC (SiO ₂ , petroleum ether: ethyl acetate = 5:1) to obtain ( R )-(2-(5-(1-((7-bromo- 4-(Trifluoromethyl)

-1-yl)amino)ethyl)thiophen-2-yl)benzyl)(methyl)tert-butyl carbamate (46.0 mg, 74.0 µmol, 25.6% yield).

-1-基)胺基)乙基)噻吩-2-基)苯甲基)(甲基)胺甲酸第三丁酯（0.046 g，74.0 µmol，1.00當量）、

啉（7.74 mg，88.8 µmol，7.82 µL，1.20當量）、Cs₂ CO₃ （72.3 mg，222 µmol，3.00當量）、Pd₂ (dba)₃ （6.78 mg，7.40 µmol，0.100當量）及RuPhos（6.91 mg，14.8 µmol，0.20當量）於二

烷（0.10 mL）中之混合物脫氣且用氮氣沖洗3次，且隨後將混合物在氮氣氛圍下在110℃下攪拌1小時。在此時間後，將混合物用水（2.00 mL）稀釋，且用乙酸乙酯（2.00 mL×3）萃取。將合併之有機層用鹽水（2.00 mL×2）洗滌，經無水硫酸鈉乾燥，過濾且在減壓下濃縮，得到殘餘物。將殘餘物藉由製備型TLC（SiO₂ ，石油醚:乙酸乙酯＝3:1）純化，得到呈黃色油狀之(R )-甲基(2-(5-(1-((7-

啉基-4-(三氟甲基)呔

-1-基)胺基)乙基)噻吩-2-基)苯甲基)胺甲酸第三丁酯（43.0 mg，68.5 µmol，92.6%產率）。Step E: Add ( R )-(2-(5-(1-((7-bromo-4-(trifluoromethyl)

-1-yl)amino)ethyl)thiophen-2-yl)benzyl)(methyl) tertiary butyl carbamate (0.046 g, 74.0 µmol, 1.00 equivalent),

Morin (7.74 mg, 88.8 µmol, 7.82 µL, 1.20 equivalents), Cs ₂ CO ₃ (72.3 mg, 222 µmol, 3.00 equivalents), Pd ₂ (dba) ₃ (6.78 mg, 7.40 µmol, 0.100 equivalents) and RuPhos (6.91 mg, 14.8 µmol, 0.20 equivalent) in two

The mixture in alkane (0.10 mL) was degassed and flushed with nitrogen 3 times, and then the mixture was stirred at 110°C for 1 hour under a nitrogen atmosphere. After this time, the mixture was diluted with water (2.00 mL), and extracted with ethyl acetate (2.00 mL×3). The combined organic layer was washed with brine (2.00 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by preparative TLC (SiO ₂ , petroleum ether: ethyl acetate = 3:1) to obtain ( R )-methyl (2-(5-(1-((7-

Linyl-4-(trifluoromethyl)

-1-yl)amino)ethyl)thiophen-2-yl)benzyl)tert-butyl carbamate (43.0 mg, 68.5 µmol, 92.6% yield).

啉基-4-(三氟甲基)呔

-1-基)胺基)乙基)噻吩-2-基)苯甲基)胺甲酸第三丁酯（50.0 mg，79.7 µmol，1.00當量）於二氯甲烷（1.00 mL）中之溶液中添加三氟乙酸（770 mg，6.75 mmol，0.50 mL，84.8當量）。將混合物在25℃下攪拌20分鐘後，隨後過濾且在減壓下濃縮，得到殘餘物。將殘餘物藉由製備型HPLC（管柱：Phenomenex Synergi C18 100×21.2 mm×4 um；移動相：A相：[水（0.1% TFA）]，B相：CAN；B%：17%-47%）純化，得到呈白色固體狀之(R) -N -(1-(5-(2-((甲基胺基)甲基)苯基)噻吩-2-基)乙基)-7-

啉基-4-(三氟甲基)呔

-1-胺（17.5 mg，33.1 µmol，41.6%產率）。Step F: To ( R )-methyl(2-(5-(1-((7-

Linyl-4-(trifluoromethyl)

-1-yl)amino)ethyl)thiophen-2-yl)benzyl) tertiary butyl carbamate (50.0 mg, 79.7 µmol, 1.00 equivalent) in dichloromethane (1.00 mL) was added Trifluoroacetic acid (770 mg, 6.75 mmol, 0.50 mL, 84.8 equivalents). After the mixture was stirred at 25°C for 20 minutes, it was then filtered and concentrated under reduced pressure to obtain a residue. The residue was subjected to preparative HPLC (column: Phenomenex Synergi C18 100×21.2 mm×4 um; mobile phase: A phase: [water (0.1% TFA)], B phase: CAN; B%: 17%-47 %) Purification to obtain (R) -N -(1-(5-(2-((methylamino)methyl)phenyl)thiophen-2-yl)ethyl)-7- as a white solid

Linyl-4-(trifluoromethyl)

-1-amine (17.5 mg, 33.1 µmol, 41.6% yield).

¹ H NMR (500 MHz, DMSO- d ₆ ) δ 8.87 (s, 2H), 8.50 (s, 1H), 7.89-7.39 (m, 6H), 7.19 (s, 1H), 7.08 (s, 1H), 6.07-5.96 (m, 1H), 4.23 (s, 2H), 3.80 (s, 4H), 3.46 (s, 4H), 2.56 (s, 3H), 1.80 (d, J = 6.9 Hz, 3H).

4-(1-甲基-4-(((R )-1-(2-甲基-3-(三氟甲基)苯基)乙基)胺基)呔

-6-基)哌啶-2-酮 ¹ H NMR (400 MHz, CD₃ OD) δ 8.70 (s, 1H), 8.39 (d,J = 8.5 Hz, 1H), 8.17 (dd,J = 8.5, 1.6 Hz, 1H), 7.74 (d,J = 7.9 Hz, 1H), 7.56 (s, 1H), 7.31 (s, 1H), 5.63 - 5.55 (m, 1H), 3.59 - 3.49 (m, 2H), 2.89 (s, 3H), 2.77 - 2.68 (m, 2H), 2.66 (s, 3H), 2.29 - 2.22 (m, 3H), 1.73 (d,J = 6.9 Hz, 3H)。LCMS [M+1]⁺ : 443.2 10-4

(R )-N -(1-(3-(二氟甲基)-2-甲基苯基)乙基)-4-甲基-7-(哌

-1-基)呔

-1-胺 ¹ H NMR (400 MHz, CD₃ OD) δ = 8.25 (d,J = 9.2 Hz, 1H), 7.96 (s, 1H), 7.83 (dd,J = 2.4, 9.2 Hz, 1H), 7.65 (d,J = 8.0 Hz, 1H), 7.40 (br d,J = 7.2 Hz, 1H), 7.30 - 7.20 (m, 1H), 7.13 - 6.80 (m, 1H), 5.6 (q,J = 6.8 Hz, 1H), 4.17 - 3.93 (m, 4H), 3.58 - 3.43 (m, 4H), 2.80 (s, 3H), 2.59 (s, 3H), 1.71 (br d,J = 6.8 Hz, 3H)。LCMS [M+1]⁺ = 412.3。 10-5

(R )-7-(6,6-二氟-1,4-二氮雜環庚烷-1-基)-4-甲基-N -(1-(2-甲基-3-(三氟甲基)苯基)乙基)呔

-1-胺 ¹ H NMR (400 MHz, CD₃ OD) δ = 7.89 (d, J = 8.8 Hz, 1H), 7.69 (d, J = 7.6 Hz, 1H), 7.56 (s, 1H), 7.53 (dd, J = 4.8, 8.8 Hz, 1H), 7.48 (d, J = 7.6 Hz, 1H), 7.22 (t, J = 8.0 Hz, 1H), 5.71 (br d, J = 6.8 Hz, 1H), 4.27 (dt, J = 2.0, 12.0 Hz, 2H), 3.89 (q,J = 4.8 Hz, 2H), 3.13 (t, J = 5.6 Hz, 2H), 3.07 (dt,J = 1.2, 14.8 Hz, 2H), 2.61 (s, 3H), 2.59 (s, 3H), 1.63 (d, J = 6.8 Hz, 3H)。LCMS [M+1]⁺ : 480.1。 10-6

4-甲基-N -((R )-1-(2-甲基-3-(三氟甲基)苯基)乙基)-7-((S )-3-甲基

啉基)呔

-1-胺 ¹ H NMR (400 MHz, CD₃ OD) δ = 8.16 (d,J = 10.0 Hz, 1H), 7.74 - 7.65 (m, 3H), 7.53 (br d,J = 7.8 Hz, 1H), 7.28 (s, 1H), 5.53 (d,J = 6.8 Hz, 1H), 5.49 (s, 1H), 4.46 - 4.36 (m, 1H), 4.12 (dd,J = 3.6, 11.2 Hz, 1H), 3.95 - 3.81 (m, 3H), 3.72 (dt,J = 2.8, 12.0 Hz, 1H), 3.51 - 3.40 (m, 1H), 3.35 (s, 1H), 2.75 (s, 3H), 2.63 (s, 3H), 1.66 (d,J = 6.8 Hz, 3H), 1.36 (d,J = 7.2 Hz, 3H)。LCMS [M+1]⁺ = 445.2。 10-7

(R)-4-甲基-N-(1-(2-甲基-3-(三氟甲基)苯基)乙基)-7-(4-(甲基胺基)哌啶-1-基)呔

-1-胺 ¹ H NMR (400 MHz, CD₃ OD) δ = 8.16 (d,J = 9.6 Hz, 1H), 7.84 (s, 1H), 7.78 - 7.71 (m, 2H), 7.52 (d,J = 7.6 Hz, 1H), 7.27 (t,J = 16.0 Hz, 1H), 5.55 - 5.50 (m, 1H), 4.54 (d,J = 13.6 Hz, 2H), 3.51 - 3.31 (m, 1H), 3.28 - 3.23 (m, 2H), 2.78 (s, 3H), 2.75 (s, 3H), 2.62 (s, 3H), 2.31 (d,J = 10.8 Hz, 2H), 1.78 - 1.72 (m, 2H), 1.68 (d,J = 7.6 Hz, 3H)。LCMS [M+1]⁺ : 458.2。 10-8

(R )-7-(4-(二甲基胺基)哌啶-1-基)-4-甲基-N -(1-(2-甲基-3-(三氟甲基)苯基)乙基)呔

-1-胺 ¹ H NMR (400MHz, CD₃ OD) δ = 8.17 (d,J = 9.6 Hz, 1H), 7.85 (s, 1H), 7.78 - 7.72 (m, 2H), 7.52 (d,J = 8.0 Hz, 1H), 7.27 (t,J = 8.0 Hz, 1H), 5.56 - 5.50 (m, 1H), 4.60 (d,J = 13.2 Hz, 2H), 3.66 - 3.63 (m, 1H), 3.30 - 3.22 (m, 2H), 2.93 (s, 6H), 2.75 (s, 3H), 2.32 (d,J = 9.6 Hz, 2H), 1.91 - 1.85 (m, 2H), 1.68 (d,J = 6.8 Hz, 3H)。LCMS [M+1]⁺ : 472.2。 10-9

(R )-7-(4-胺基-4-甲基哌啶-1-基)-4-甲基-N -(1-(2-甲基-3-(三氟甲基)苯基)乙基)呔

-1-胺 ¹ H NMR (400 MHz, CD₃ OD) δ 8.17 (d,J = 9.3 Hz, 1H), 7.85 (s, 1H), 7.79 - 7.71 (m, 2H), 7.53 (d,J = 7.8 Hz, 1H), 7.27 (t,J = 7.8 Hz, 1H), 5.54 (q,J = 6.9 Hz, 1H), 4.21 (d,J = 14.1 Hz, 2H), 3.58 (dd,J = 14.1, 6.9 Hz, 2H), 2.75 (s, 3H), 2.63 (s, 3H), 2.05 - 1.97 (m, 4H), 1.68 (d,J = 6.9 Hz, 3H), 1.57 (s, 3H)。LCMS [M+1]⁺ : 458.2。 10-10

(R)-4-甲基-7-(4-(1-甲基-1H-吡唑-4-基)哌

-1-基)-N-(1-(2-甲基-3-(三氟甲基)苯基)乙基)呔

-1-胺 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 14.83 (s, 1H), 8.76 (s, 1H), 8.16 (d,J = 9.3 Hz, 1H), 8.03 (s, 1H), 7.85 - 7.79 (m, 2H), 7.56 (d,J = 7.1 Hz, 2H), 7.36 (dd,J = 16.0, 8.2 Hz, 2H), 5.48 (q,J = 6.9 Hz, 1H), 3.92 (s, 4H), 3.78 (s, 3H), 3.17 (s, 5H), 2.73 (s, 3H), 2.59 - 2.56 (m, 3H), 1.64 (d,J = 6.9 Hz, 3H)。LCMS [M+1]⁺ : 510.2 10-11

(R )-7-(1,3-二甲基-5,6-二氫咪唑并[1,5-a]吡

-7(8H )-基)-4-甲基-N -(1-(2-甲基-3-(三氟甲基)苯基)乙基)呔

-1-胺 ¹ H NMR (400 MHz, CD₃ OD) δ 8.30 (d,J = 9.3 Hz, 1H), 8.02 (d,J = 2.4 Hz, 1H), 7.92 (dd,J = 9.3, 2.5 Hz, 1H), 7.83 (d,J = 7.9 Hz, 1H), 7.57 (d,J = 7.8 Hz, 1H), 7.31 (t,J = 7.9 Hz, 1H), 5.61 (q,J = 6.9 Hz, 1H), 5.02 (d,J = 2.5 Hz, 2H), 4.43 (t,J = 5.4 Hz, 2H), 4.30 (t,J = 5.4 Hz, 2H), 2.83 (s, 3H), 2.69 - 2.65 (m, 6H), 2.43 (s, 3H), 1.76 (d,J = 7.0 Hz, 3H)。LCMS [M+1]⁺ : 495.2。 10-12

(R )-2-(1-甲基-4-(((R )-1-(2-甲基-3-(三氟甲基)苯基)乙基)胺基)呔

-6-基)六氫吡咯并[1,2-a ]吡

-6(2H )-酮 ¹ H NMR (400 MHz, DMSO-d₆ ) δ = 7.80 (d,J = 8.8 Hz, 1H), 7.75 (d,J = 7.6 Hz, 1H), 7.65 - 7.63 (m, 2H), 7.50 (d,J = 7.6 Hz, 1H), 7.36 (d,J = 6.8 Hz, 1H), 7.30 (t,J = 8.0 Hz, 1H), 5.70 - 5.66 (m, 1H), 4.24 - 4.23 (m, 1H), 4.12 - 3.96 (m, 1H), 3.94 - 3.93 (m, 1H), 3.72 - 3.71 (m, 1H), 3.09 - 3.20 (m, 1H), 2.91 - 3.02 (m, 1H), 2.60 - 2.71 (m, 1H), 2.57 (s, 3H), 2.52 (s, 3H), 2.32 - 2.28 (m, 2H), 2.26 - 2.14 (m, 1H), 1.70 - 1.68 (m, 1H), 1.55 (d,J = 6.8 Hz, 3H)。LCMS [M+1]⁺ : 484.1。 10-13

(S )-2-(1-甲基-4-(((R )-1-(2-甲基-3-(三氟甲基)苯基)乙基)胺基)呔

-6-基)六氫吡咯并[1,2-a ]吡

-6(2H )-酮 ¹ H NMR (400 MHz, DMSO-d₆ ) δ = 7.80 (d,J = 8.8 Hz, 1H), 7.73 (d,J = 8.0 Hz, 1H), 7.64 - 7.60 (m, 2H), 7.50 (d,J = 7.6 Hz, 1H), 7.29 (t,J = 8.0 Hz, 1H), 5.68 - 5.63 (m, 1H), 4.22 (d,J = 10.4 Hz, 1H), 4.13 (d,J = 12.4 Hz, 1H), 4.09 - 3.95 (m, 1H), 3.72 - 3.71 (m, 1H), 2.97 (t,J = 9.2 Hz, 1H), 2.81 (t,J = 12.0 Hz, 1H), 2.67 - 2.61 (m, 1H), 2.56 (s, 3H), 2.51 (s, 3H), 2.32 - 2.29 (m, 2H), 2.26 - 2.14 (m, 1H), 1.70 - 1.68 (m, 1H), 1.53 (d,J = 7.2 Hz, 3H)。LCMS [M+1]⁺ : 484.1。 10-14

(R)-7-(3,5-二甲基-1H-吡唑-1-基)-4-甲基-N-(1-(2-甲基-3-(三氟甲基)苯基)乙基)呔

-1-胺 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.01 (brs, 1H), 8.95 (s, 1H), 8.47 (d,J = 8.8 Hz, 1H), 8.31 (d,J = 8.0 Hz, 1H), 7.77 (d,J = 7.6 Hz, 1H), 7.58 (d,J = 8.0 Hz, 1H), 7.37 (m, 1H), 6.3 (s, 1H), 5.51(m, 1H), 2.84 (s, 3H), 2.58 (s, 3H), 2.49 (s, 3H), 2.28 (s, 3H), 1.63 (d,J = 6.8 Hz, 3H)。LCMS [M+H]⁺ : 440.6。 10-15

(R )-7-(5,6-二氫吡咯并[3,4-c ]吡唑-1(4H )-基)-4-甲基-N -(1-(2-甲基-3-(三氟甲基)苯基)乙基)呔

-1-胺 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.77 - 8.71 (m, 1H), 8.13 - 8.08 (m, 1H), 8.03 - 7.98 (m, 1H), 7.93 (br d,J = 6.4 Hz, 1H), 7.79 (d,J = 8.0 Hz, 1H), 7.70 (s, 1H), 7.51 (d,J = 7.6 Hz, 1H), 7.30 (t,J = 6.8 Hz, 1H), 5.74 - 5.63 (m, 1H), 4.66 - 4.52 (m, 2H), 4.15 - 4.05 (m, 2H), 2.64 (s, 3H), 2.59 (br s, 3H), 1.56 (d,J = 6.8 Hz, 3H)。LCMS [M+1]⁺ : 453.3。 10-16

(R )-7-(5,6-二氫吡咯并[3,4-c ]吡唑-2(4H )-基)-4-甲基-N -(1-(2-甲基-3-(三氟甲基)苯基)乙基)呔

-1-胺 ¹ H NMR (400 MHz, CD₃ OD) δ = 8.75 (d,J = 2.0 Hz, 1H), 8.42 - 8.34 (m, 2H), 8.17 (d,J = 8.8 Hz, 1H), 7.75 (d,J = 8.0 Hz, 1H), 7.50 (d,J = 7.6 Hz, 1H), 7.25 (t,J = 8.0 Hz, 1H), 5.74 (q,J = 6.8 Hz, 1H), 4.42 (d,J = 7.2 Hz, 4H), 2.71 (s, 3H), 2.64 (s, 3H), 1.66 (d,J = 6.8 Hz, 3H)。LCMS [M+1]⁺ : 453.4。 10-17

(R )-4-甲基-N -(1-(2-甲基-3-(三氟甲基)苯基)乙基)-7-(1H -吡唑-1-基)呔

-1-胺 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.20 (s, 1H), 8.98 (br s, 1H), 8.87 (d,J = 2.8 Hz, 1H), 8.65 (dd,J = 9.2 Hz,J = 2.0 Hz 1H) , 8.51 (d,J = 8.8 Hz, 1H), 8.03 (d,J = 1.6 Hz, 1H), 7.81 (d,J = 7.6 Hz, 1H), 7.59 (d,J = 7.6 Hz, 1H) , 7.38 (m, 1H), 6.81 (m, 1H) , 5.52 (m, 1H) , 2.83 (s, 3H) , 2.59 (s, 3H) , 1.66 (d,J = 6.8 Hz, 3H)。LCMS [M+H]⁺ : 412.3。 10-18

(R )-4-甲基-N -(1-(2-甲基-3-(三氟甲基)苯基)乙基)-7-(1,8-二氮雜螺[4.5]癸-8-基)呔

-1-胺 ¹ H NMR (400 MHz, CD₃ OD) δ = 8.18 (d,J = 9.2 Hz, 1H), 7.89 (d,J = 2.4 Hz, 1H), 7.82 - 7.74 (m, 2H), 7.54 (d,J = 8.0 Hz, 1H), 7.29 (t,J = 7.6 Hz, 1H), 5.55 (q,J = 7.2 Hz, 1H), 4.28 - 4.16 (m, 2H), 3.70 - 3.57 (m, 2H), 3.47 (t,J = 6.8 Hz, 2H), 2.77 (s, 3H), 2.65 (s, 3H), 2.32 - 2.17 (m, 4H), 2.17 - 2.06 (m, 4H), 1.71 (d,J = 7.2 Hz, 3H)。LCMS [M+1]⁺ : 484.2。 10-19

(R )-4-甲基-N -(1-(2-甲基-3-(三氟甲基)苯基)乙基)-7-(1-甲基-1,8-二氮雜螺[4.5]癸-8-基)呔

-1-胺 ¹ H NMR (400 MHz, CD₃ OD) δ = 8.19 (d,J = 9.2 Hz, 1H), 7.91 (d,J = 2.0 Hz, 1H), 7.84 - 7.74 (m, 2H), 7.54 (d,J = 8.0 Hz, 1H), 7.29 (t,J = 7.6 Hz, 1H), 5.56 (q,J = 6.8 Hz, 1H), 4.62 - 4.50 (m, 2H), 3.83 - 3.71 (m, 1H), 3.42 - 3.33 (m, 3H), 2.85 (s, 3H), 2.77 (s, 3H), 2.65 (s, 3H), 2.62 - 2.53 (m, 1H), 2.35 - 2.14 (m, 4H), 2.13 - 1.93 (m, 3H), 1.71 (d,J = 7.2 Hz, 3H)。LCMS [M+1]⁺ : 498.3。 10-20

(R )-N -(1-(2,4-二氯苯基)乙基)-4-甲基-7-

啉基呔

-1-胺 ¹ H NMR (400 MHz, DMSO-d₆ ) δ = 7.82 (d,J = 9.2 Hz, 1H), 7.63 - 7.62 (m, 1H), 7.57 - 7.56 (m, 2H), 7.44 (d,J = 8.0 Hz, 1H), 7.41 - 7.39 (m, 1H), 7.32 - 7.31 (m, 1H), 5.64 - 5.60 (m, 1H), 3.82 (t,J = 4.8 Hz, 4H), 3.41 (t,J = 4.4 Hz, 4H), 2.52 (s, 3H), 1.55 (d,J = 7.2 Hz, 3H)。LCMS [M+1]⁺ : 417.0。 10-21

(R )-N -(1-(2,4-二氯苯基)乙基)-4-甲基-7-(哌

-1-基)呔

-1-胺 ¹ H NMR (400 MHz, DMSO-d₆ ) δ = 14.96 (s, 1H), 9.60 (s, 2H), 9.05 (s, 1H), 8.22 - 8.21 (m, 2H), 7.82 - 7.77 (m, 1H), 7.65 (d,J = 8.4 Hz, 1H), 7.60 (d,J = 2.4 Hz, 1H), 7.37 (dd,J = 2.0 Hz, 8.4 Hz, 1H), 5.50 - 5.43 (m, 1H), 4.07 - 3.98 (m, 4H), 3.33 - 3.28 (m, 4H), 2.74 (s, 3H), 1.66 (d,J = 6.8 Hz, 3H)。LCMS [M+1]⁺ : 416.1。 10-22

7-(6-氟-1,4-二氮雜環庚烷-1-基)-4-甲基-N -((R )-1-(2-甲基-3-(三氟甲基)苯基)乙基)呔

-1-胺 ¹ H NMR (400 MHz, DMSO-d₆ ) δ = 7.88 (d,J = 9.2 Hz, 1H), 7.69 (d,J = 7.6 Hz, 1H), 7.51 - 7.47 (m, 3H), 7.22 (t,J = 8.0 Hz, 1H), 5.71 - 5.68 (m, 1H), 5.14 - 4.94 (m, 1H), 4.13 - 4.07 (m, 2H), 3.85 - 3.83 (m, 2H), 3.30 - 2.99 (m, 4H), 2.61 - 2.55 (m, 6H), 1.61 (d,J = 6.8 Hz, 3H)。LCMS [M+1]⁺ : 462.2。 10-23

(R )-4-(1-甲基-4-((1-(2-甲基-3-(三氟甲基)苯基)乙基)胺基)呔

-6-基)硫

啉1,1-二氧化物 ¹ H NMR (400 MHz, CD₃ OD) δ = 7.95 (d,J = 8.8 Hz, 1H), 7.73 - 7.68 (m, 2H), 7.64 (dd,J = 2.4, 8.8 Hz, 1H), 7.48 (d,J = 7.6 Hz, 1H), 7.23 (t,J = 7.6 Hz, 1H), 5.72 (q,J = 6.8 Hz, 1H), 4.20 - 4.11 (m, 4H), 3.25 - 3.17 (m, 4H), 2.61 (s, 6H), 1.63 (d,J = 7.2 Hz, 3H)。LCMS [M+1]⁺ : 479.2。 10-24

4-甲基-N -((R )-1-(2-甲基-3-(三氟甲基)苯基)乙基)-7-(((S )-1-甲基吡咯啶-2-基)甲氧基)呔

-1-胺鹽酸鹽 ¹ H NMR (400 MHz, CD₃ OD) δ = 8.40 - 8.36 (m, 2H), 7.88 - 7.77 (m, 2H), 7.54 (d,J = 8.0 Hz, 1H), 7.28 (t,J = 8.0 Hz, 1H), 5.58 (q,J = 6.8 Hz, 1H), 4.69 (br dd,J = 7.2, 11.2 Hz, 2H), 4.08 (br d,J = 3.6 Hz, 1H), 3.81 (br s, 1H), 3.15 (s, 3H), 2.86 (s, 3H), 2.64 (s, 3H), 2.51 (br dd,J = 6.0, 12.4 Hz, 1H), 2.45 - 2.04 (m, 4H), 1.73 (d,J = 6.8 Hz, 3H)。LCMS [M+1]⁺ : 459.2。 10-25

4-甲基-N -((R )-1-(2-甲基-3-(三氟甲基)苯基)乙基)-7-(((R )-1-甲基吡咯啶-2-基)甲氧基)呔

-1-胺鹽酸鹽 ¹ H NMR (400 MHz, CD₃ OD) δ = 8.48 - 8.29 (m, 2H), 7.89 - 7.79 (m, 2H), 7.56 (br d,J = 7.6 Hz, 1H), 7.30 (br t,J = 8.0 Hz, 1H), 5.63 - 5.54 (m, 1H), 4.85 - 4.67 (m, 3H), 4.15 - 4.05 (m, 1H), 3.89 - 3.79 (m, 1H), 3.17 (s, 3H), 2.88 (s, 3H), 2.66 (s, 3H), 2.60 - 2.44 (m, 1H), 2.36 - 2.10 (m, 3H), 1.74 (br d,J = 6.8 Hz, 3H)。LCMS [M+1]⁺ : 459.2。 10-26

7-((R )-3-(二甲基胺基)吡咯啶-1-基)-4-甲基-N -((R )-1-(2-甲基-3-(三氟甲基)苯基)乙基)呔

-1-胺鹽酸鹽 ¹ H NMR (400 MHz, CD₃ OD) δ = 8.22 (d,J = 9.2 Hz, 1H), 7.79 (d,J = 7.6 Hz, 1H), 7.60 (d,J = 2.0 Hz, 1H), 7.54 (d,J = 8.0 Hz, 1H), 7.49 (dd,J = 2.4, 9.2 Hz, 1H), 7.29 (t,J = 8.0 Hz, 1H), 5.57 (q,J = 6.8 Hz, 1H), 4.26 - 4.17 (m, 2H), 4.06 - 3.96 (m, 1H), 3.95 - 3.85 (m, 1H), 3.78 - 3.67 (m, 1H), 3.09 (br d,J = 10.4 Hz, 6H), 2.78 (s, 3H), 2.77 - 2.70 (m, 1H), 2.65 (s, 3H), 2.47 (qd,J = 8.4, 12.4 Hz, 1H), 1.72 (d,J = 6.8 Hz, 3H)。LCMS [M+1]⁺ : 458.2。 10-27

7-((S )-3-(二甲基胺基)吡咯啶-1-基)-4-甲基-N -((R )-1-(2-甲基-3-(三氟甲基)苯基)乙基)呔

-1-胺鹽酸鹽 ¹ H NMR (400 MHz, CD₃ OD) δ = 8.20 (d,J = 9.2 Hz, 1H), 7.77 (d,J = 7.6 Hz, 1H), 7.59 (d,J = 1.6 Hz, 1H), 7.52 (br d,J = 8.0 Hz, 1H), 7.47 (dd,J = 2.4, 9.2 Hz, 1H), 7.27 (t,J = 7.6 Hz, 1H), 5.55 (q,J = 6.8 Hz, 1H), 4.27 - 4.12 (m, 2H), 4.01 - 3.88 (m, 2H), 3.77 - 3.67 (m, 1H), 3.07 (br s, 6H), 2.76 (s, 3H), 2.74 - 2.69 (m, 1H), 2.63 (s, 3H), 2.46 (qd,J = 8.8, 12.8 Hz, 1H), 1.70 (d,J = 7.2 Hz, 3H)。LCMS[M+1]⁺ : 458.3。 10-28

4-甲基-N -((R )-1-(2-甲基-3-(三氟甲基)苯基)乙基)-7-(3-甲基-3,8-二氮雜雙環[3.2.1]辛-8-基)呔

-1-胺 鹽酸鹽 ¹ H NMR (400 MHz, CD₃ OD) δ = 8.25 (d,J = 9.2 Hz, 1H), 7.94 (d,J = 2.4 Hz, 1H), 7.80 (d,J = 8.0 Hz, 1H), 7.74 (dd,J = 2.4, 9.2 Hz, 1H), 7.54 (d,J = 7.6 Hz, 1H), 7.29 (t,J = 7.6 Hz, 1H), 5.56 (q,J = 6.8 Hz, 1H), 5.07 (br s, 2H), 3.60 (br d,J = 12.8 Hz, 2H), 3.40 - 3.34 (m, 2H), 2.87 (s, 3H), 2.79 (s, 3H), 2.65 (s, 3H), 2.47 - 2.24 (m, 4H), 1.72 (d,J = 6.8 Hz, 3H)。LCMS [M+1]⁺ : 470.2。 10-29

4-甲基-N -((R )-1-(2-甲基-3-(三氟甲基)苯基)乙基)-7-(8-甲基-3,8-二氮雜雙環[3.2.1]辛-3-基)呔

-1-胺 鹽酸鹽 ¹ H NMR (400 MHz, CD₃ OD): δ = 8.28-8.21 (m, 1H), 7.94-7.90 (m, 1H), 7.81-7.73 (m, 2H), 7.55-7.50 (m, 1H), 7.31-7.24 (m, 1H), 5.60-5.51 (m, 1H), 4.43-4.32 (m, 2H), 4.28-4.21 (m, 2H), 3.84-3.58 (m, 2H), 3.01-2.91 (m, 3H), 2.83-2.76 (m, 3H), 2.65-2.60 (m, 3H), 2.49-2.33 (m, 2H), 2.25-2.12 (m, 2H), 1.74-1.66 (m, 3H)。LCMS [M+1]⁺ : 470.3。 10-30

(R )-7-(4-(氮雜環丁烷-1-基)哌啶-1-基)-4-甲基-N -(1-(2-甲基-3-(三氟甲基)苯基)乙基)呔

-1-胺 鹽酸鹽 ¹ H NMR (400 MHz, CD₃ OD) δ = 8.17 (d,J = 9.6 Hz, 1H), 7.86 (d,J = 2.4 Hz, 1H), 7.81 - 7.72 (m, 2H), 7.54 (d,J = 7.6 Hz, 1H), 7.34 - 7.25 (m, 1H), 5.55 (q,J = 7.2 Hz, 1H), 4.54 (br d,J = 13.6 Hz, 2H), 4.39 - 4.13 (m, 4H), 3.65 (tt,J = 4.0, 11.2 Hz, 1H), 3.27 (br t,J = 12.4 Hz, 2H), 2.77 (s, 3H), 2.65 (s, 4H), 2.54 - 2.34 (m, 1H), 2.24 (br d,J = 11.6 Hz, 2H), 1.70 (d,J = 6.8 Hz, 3H), 1.67 - 1.52 (m, 2H)。LCMS [M+1]⁺ : 484.3。 10-31

4-甲基-N -((R )-1-(2-甲基-3-(三氟甲基)苯基)乙基)-7-((1S ,4S )-5-甲基-2,5-二氮雜雙環[2.2.2]辛-2-基)呔

-1-胺 ¹ H NMR (400 MHz, CD₃ OD) δ = 8.04 (d,J = 9.2 Hz, 1H), 7.70 (d,J = 8.0 Hz, 1H), 7.51 (d,J = 7.6 Hz, 1H), 7.48 - 7.42 (m, 2H), 7.26 (t,J = 8.0 Hz, 1H), 5.57 (q,J = 6.8 Hz, 1H), 4.44 (br s, 1H), 4.02 (td,J = 2.4, 11.6 Hz, 1H), 3.52 (dd,J = 2.0, 11.6 Hz, 1H), 3.16 - 3.02 (m, 3H), 2.68 (s, 3H), 2.62 (s, 3H), 2.54 (s, 3H), 2.33 - 2.20 (m, 1H), 2.13 - 1.92 (m, 2H), 1.84 - 1.73 (m, 1H), 1.65 (d,J = 6.8 Hz, 3H)。LCMS [M+1]⁺ : 470.2。 10-32

4-甲基-N -((R )-1-(2-甲基-3-(三氟甲基)苯基)乙基)-7-((1R ,4R )-5-甲基-2,5-二氮雜雙環[2.2.2]辛-2-基)呔

-1-胺 ¹ H NMR (400 MHz, CD₃ OD) δ = 7.85 (d,J = 8.8 Hz, 1H), 7.70 (d,J = 7.6 Hz, 1H), 7.47 (d,J = 7.6 Hz, 1H), 7.33 (dd,J = 2.4, 8.8 Hz, 1H), 7.28 (d,J = 2.4 Hz, 1H), 7.22 (t,J = 8.0 Hz, 1H), 5.71 (q,J = 6.8 Hz, 1H), 4.30 (br s, 1H), 3.96 (td,J = 2.4, 10.8 Hz, 1H), 3.43 (dd,J = 2.0, 10.8 Hz, 1H), 3.11 - 2.94 (m, 3H), 2.61 (s, 3H), 2.57 (s, 3H), 2.49 (s, 3H), 2.28 - 2.16 (m, 1H), 2.10 - 1.99 (m, 1H), 1.97 - 1.87 (m, 1H), 1.81 - 1.69 (m, 1H), 1.62 (d,J = 6.8 Hz, 3H)。LCMS [M+1]⁺ : 470.2。 10-33

(R )-4-甲基-N -(1-(2-甲基-3-(三氟甲基)苯基)乙基)-7-(4-甲基-4,7-二氮雜螺[2.5]辛-7-基)呔

-1-胺 ¹ H NMR (400 MHz, CD₃ OD) δ = 7.88 (d,J = 8.8 Hz, 1H), 7.69 (d,J = 7.6 Hz, 1H), 7.58 - 7.52 (m, 2H), 7.47 (d,J = 7.6 Hz, 1H), 7.22 (t,J = 8.0 Hz, 1H), 5.72 (q,J = 6.8 Hz, 1H), 3.54 (dd,J = 4.8, 6.8 Hz, 2H), 3.35 (s, 2H), 3.18 - 3.11 (m, 2H), 2.64 - 2.57 (m, 6H), 2.48 (s, 3H), 1.62 (d,J = 6.8 Hz, 3H), 0.86 - 0.80 (m, 2H), 0.73 - 0.64 (m, 2H).LCMS [M+1]⁺ : 470.3. 10-34

(R )-4-甲基-N -(1-(2-甲基-3-(三氟甲基)苯基)乙基)-7-(4,7-二氮雜螺[2.5]辛-7-基)呔

-1-胺 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.46 (br s, 1H), 8.06 (d,J = 9.2 Hz, 1H), 7.90 (br s, 1H), 7.81 (br d,J = 7.6 Hz, 1H), 7.72 (br d,J = 8.0 Hz, 1H), 7.54 (d,J = 7.6 Hz, 1H), 7.34 (br t,J = 8.0 Hz, 1H), 5.51 (br t,J = 6.8 Hz, 1H), 3.84 (br d,J = 4.8 Hz, 2H), 3.73 (br s, 2H), 3.25 (br s, 2H), 2.67 (s, 3H), 2.57 (s, 3H), 1.62 (br d,J = 6.8 Hz, 3H), 0.95 - 0.79 (m, 4H)。LCMS [M+1]⁺ : 456.2。 10-35

(R )-4-甲基-N -(1-(2-甲基-3-(三氟甲基)苯基)乙基)-7-(1,8-二氮雜螺[4.5]癸-8-基)呔

-1-胺 ¹ H NMR (400 MHz, CD₃ OD) δ = 8.18 (d,J = 9.2 Hz, 1H), 7.89 (d,J = 2.4 Hz, 1H), 7.82 - 7.74 (m, 2H), 7.54 (d,J = 8.0 Hz, 1H), 7.29 (t,J = 7.6 Hz, 1H), 5.55 (q,J = 7.2 Hz, 1H), 4.28 - 4.16 (m, 2H), 3.70 - 3.57 (m, 2H), 3.47 (t,J = 6.8 Hz, 2H), 2.77 (s, 3H), 2.65 (s, 3H), 2.32 - 2.17 (m, 4H), 2.17 - 2.06 (m, 4H), 1.71 (d,J = 7.2 Hz, 3H)。LCMS [M+1]⁺ : 484.2。 10-36

(R )-4-甲基-N -(1-(2-甲基-3-(三氟甲基)苯基)乙基)-7-(2,8-二氮雜螺[4.5]癸-8-基)呔

-1-胺 鹽酸鹽 ¹ H NMR (400 MHz, CD₃ OD) δ = 8.15 (d,J = 9.6 Hz, 1H), 7.83 (d,J = 2.4 Hz, 1H), 7.78 - 7.71 (m, 2H), 7.54 (d,J = 7.6 Hz, 1H), 7.29 (t,J = 8.0 Hz, 1H), 5.55 (q,J = 6.8 Hz, 1H), 3.95 - 3.75 (m, 4H), 3.50 (t,J = 7.2 Hz, 2H), 3.28 (s, 2H), 2.76 (s, 3H), 2.65 (s, 3H), 2.15 - 2.08 (m, 2H), 1.96 - 1.83 (m, 4H), 1.70 (d,J = 6.8 Hz, 3H)。LCMS [M+1]⁺ : 484.2。 10-37

(R )-4-甲基-N -(1-(2-甲基-3-(三氟甲基)苯基)乙基)-7-(2-甲基-2,8-二氮雜螺[4.5]癸-8-基)呔

-1-胺 鹽酸鹽 ¹ H NMR (400 MHz, CD₃ OD) δ = 8.15 (d,J = 9.2 Hz, 1H), 7.81 (d,J = 2.0 Hz, 1H), 7.77 - 7.69 (m, 2H), 7.54 (d,J = 7.6 Hz, 1H), 7.29 (t,J = 8.0 Hz, 1H), 5.55 (q,J = 6.8 Hz, 1H), 3.94 - 3.70 (m, 6H), 3.31 - 3.24 (m, 1H), 3.08 (d,J = 11.6 Hz, 1H), 3.01 (s, 3H), 2.76 (s, 3H), 2.64 (s, 3H), 2.33 - 2.21 (m, 1H), 2.17 - 2.08 (m, 1H), 2.01 - 1.87 (m, 4H), 1.69 (d,J = 6.8 Hz, 3H)。LCMS [M+1]⁺ : 498.3。 10-38

(R )-8-(1-甲基-4-((1-(2-甲基-3-(三氟甲基)苯基)乙基)胺基)呔

-6-基)-2,8-二氮雜螺[4.5]癸-1-酮 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 7.81-7.74 (m, 2H), 7.63-7.58 (m, 3H), 7.50 (d,J = 7.6 Hz, 1H), 7.55-7.44 (m, 1H), 7.32-7.29 (m, 1H), 5.68-5.64 (m, 1H), 4.05-4.01 (m, 2H), 3.21-3.23 (m, 1H), 3.08-3.13 (m, 3H), 2.57 (s, 3H), 2.53 (s, 3H), 2.06 (t,J = 6.8 Hz, 2H), 1.85-1.78 (m, 2H), 1.55 (d,J = 6.8 Hz, 3H), 1.50-1.52(m, 2H)。LCMS [M+1]⁺ : 498.6。 10-39

(R )-2-(1-甲基-4-((1-(2-甲基-3-(三氟甲基)苯基)乙基)胺基)呔

-6-基)-2,8-二氮雜螺[4.5]癸-1-酮 鹽酸鹽 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.40 (br s, 1H), 9.17 (br s, 1H), 9.08 - 8.94 (m, 1H), 8.89 (dd,J = 1.2, 8.8 Hz, 1H), 8.70 (s, 1H), 8.39 (d,J = 9.2 Hz, 1H), 7.92 (d,J = 8.0 Hz, 1H), 7.54 (d,J = 7.6 Hz, 1H), 7.33 (t,J = 8.0 Hz, 1H), 5.50 (q,J = 6.4 Hz, 1H), 4.29 - 4.19 (m, 1H), 4.15 - 4.09 (m, 1H), 3.36 - 3.27 (m, 2H), 3.12 - 3.01 (m, 2H), 2.82 (s, 3H), 2.57 (s, 3H), 2.26 (br t,J = 6.8 Hz, 2H), 2.10 - 1.98 (m, 2H), 1.83 (br d,J = 12.8 Hz, 2H), 1.66 (d,J = 6.8 Hz, 3H)。LCMS [M+1]⁺ : 498.3。 10-40

(R )-2-甲基-8-(1-甲基-4-((1-(2-甲基-3-(三氟甲基)苯基)乙基)胺基)呔

-6-基)-2,8-二氮雜螺[4.5]癸-1-酮 ¹ H NMR (400 MHz, CD₃ OD) δ = 8.12 (br d,J = 9.2 Hz, 1H), 7.81 - 7.64 (m, 3H), 7.52 (br d,J = 7.6 Hz, 1H), 7.27 (br t,J = 7.6 Hz, 1H), 5.52 (q,J = 6.8 Hz, 1H), 4.31 (br d,J = 13.6 Hz, 2H), 3.55 - 3.39 (m, 4H), 2.88 (s, 3H), 2.73 (s, 3H), 2.63 (s, 3H), 2.20 (br t,J = 6.8 Hz, 2H), 1.98 (br t,J = 12.8 Hz, 2H), 1.66 (br d,J = 7.2 Hz, 5H)。LCMS [M+1]⁺ : 512.2。 10-41

(R )-4-甲基-N -(1-(2-甲基-3-(三氟甲基)苯基)乙基)-7-(6-甲基-2,6-二氮雜螺[3.4]辛-2-基)呔

-1-胺 鹽酸鹽 ¹ H NMR (400 MHz, CD₃ OD) δ = 8.14 (d,J = 9.2 Hz, 1H), 7.71 (d,J = 8.0 Hz, 1H), 7.55 - 7.49 (m, 1H), 7.55 - 7.47 (m, 1H), 7.43 - 7.40 (m, 1H), 7.43 - 7.38 (m, 1H), 7.27 (t,J = 7.6 Hz, 1H), 7.18 (d,J = 2.0, 8.8 Hz, 1H), 5.52 (q,J = 7.2 Hz, 1H), 4.44 - 4.32 (m, 2H), 4.32 - 4.23 (m, 1H), 4.19 - 4.04 (m, 1H), 3.85 - 3.69 (m, 1H), 3.52 - 3.43 (m, 1H), 3.01 (s, 2H), 2.77 - 2.71 (m, 3H), 2.70 - 2.59 (m, 4H), 2.57 - 2.49 (m, 1H), 2.57 - 2.49 (m, 1H), 1.73 - 1.63 (m, 3H)。LCMS [M+1]⁺ : 470.2。 10-42

(R )-7-(4-(二甲基胺基)-4-甲基哌啶-1-基)-4-甲基-N -(1-(2-甲基-3-(三氟甲基)苯基)乙基)呔

-1-胺 鹽酸鹽 ¹ H NMR (400 MHz, CD₃ OD) δ = 8.17 (d,J = 9.2 Hz, 1H), 7.87 (d,J = 2.8 Hz, 1H), 7.78 - 7.73 (m, 2H), 7.52 (d,J = 7.6 Hz, 1H), 7.27 (t,J = 8.0 Hz, 1H), 5.54 (q,J = 6.8 Hz, 1H), 4.50 - 4.42 (m, 2H), 3.42 - 3.34 (m, 2H), 2.88 (s, 6H), 2.75 (s, 3H), 2.63 (s, 3H), 2.24 - 2.15 (m, 2H), 2.12 - 2.01 (m, 2H), 1.69 (d,J = 6.8 Hz, 3H), 1.57 (s, 3H)。LCMS [M+1]⁺ : 486.3。 10-43

(R )-4-甲基-N -(1-(萘-1-基)乙基)-7-(哌

-1-基)呔

-1-胺 甲酸鹽 ¹ H NMR (400 MHz, CD₃ OD) δ = 8.49 (s, 1H), 8.19 (d,J = 8.0 Hz, 1H), 8.10 (d,J = 9.2 Hz, 1H), 7.92 - 7.83 (m, 1H), 7.78 - 7.73 (m, 2H), 7.71 - 7.67 (m, 1H), 7.63 (d,J = 7.2 Hz, 1H), 7.53 - 7.44 (m, 2H), 7.43 - 7.37 (m, 1H), 6.23 - 6.09 (m, 1H), 3.79 - 3.69 (m, 4H), 3.27 - 3.19 (m, 4H), 2.71 (s, 3H), 1.82 (d,J = 6.8 Hz, 3H)。LCMS [M+1]⁺ : 398.2。 10-44

(R)-7-(4-(氮雜環丁烷-1-基)哌啶-1-基)-N-(1-(3-(二氟甲基)-2-甲基苯基)乙基)-4-甲基呔

-1-胺 鹽酸鹽 ¹ H NMR (400 MHz, DMSO-d₆ ) δ = 8.69 - 8.52 (m, 1H), 8.11 (br d,J = 9.2 Hz, 1H), 7.95 (br s, 1H), 7.76 (br d,J = 9.6 Hz, 1H), 7.67 (br s, 1H), 7.40 (br d,J = 7.6 Hz, 1H), 7.36 - 7.07 (m, 2H), 5.45 (br t,J = 6.8 Hz, 1H), 4.49 (br d,J = 13.2 Hz, 2H), 4.18 - 3.93 (m, 4H), 3.55 - 3.48 (m, 1H), 3.19 - 3.10 (m, 2H), 2.70 (s, 3H), 2.51 - 2.51 (m, 3H), 2.40 - 2.15 (m, 2H), 2.07 - 2.02 (m, 2H), 1.62 (d,J = 7.2 Hz, 3H), 1.56 - 1.41 (m, 2H)。LCMS [M+1]⁺ : 466.2。 10-45

(R)-N ⁷ ,N ⁷ ,4-三甲基-N ¹ -(1-(2-甲基-3-(三氟甲基)苯基)乙基)呔

-1,7-二胺 ¹ H NMR (400 MHz, CD₃ OD) δ = 8.12 (d,J = 8.8 Hz, 1H), 7.70 (d,J = 8.0 Hz, 1H), 7.57 - 7.44 (m, 3H), 7.27 (t,J = 8.0 Hz, 1H), 5.53 (q,J = 6.8 Hz, 1H), 3.34 - 3.32 (m, 6H), 2.80 - 2.71 (s, 3H), 2.63 (s, 3H), 1.67 (d,J = 7.2 Hz, 3H)。LCMS [M+1]⁺ : 389.2。 10-46

(R )-7-(3-(二甲基胺基)氮雜環丁烷-1-基)-4-甲基-N -(1-(2-甲基-3-(三氟甲基)苯基)乙基)呔

-1-胺 甲酸鹽 ¹ H NMR (400 MHz, CDCl₃ ) δ = 8.56 (s, 1H), 7.92 (d,J = 8.8 Hz, 1H), 7.70 (d,J = 7.6 Hz, 1H), 7.49 (d,J = 7.6 Hz, 1H), 7.28 - 7.24 (m, 1H), 7.22 (d,J = 2.4 Hz, 1H), 7.11 - 7.03 (m, 1H), 5.68 - 5.55 (m, 1H), 4.25 (t,J = 8.0 Hz, 2H), 4.02 - 3.89 (m, 2H), 3.48 - 3.37 (m, 1H), 2.62 (s, 3H), 2.61 (s, 3H), 2.29 (s, 6H), 1.63 (d,J = 6.8 Hz, 3H)。LCMS [M+1]⁺ : 444.1。 10-47

(R )-3-甲基-1-(1-甲基-4-((1-(2-甲基-3-(三氟甲基)苯基)乙基)胺基)呔

-6-基)氮雜環丁烷-3-醇 ¹ H NMR (400 MHz, CD₃ OD) δ = 7.83 (d,J = 8.8 Hz, 1H), 7.69 (d,J = 7.6 Hz, 1H), 7.47 (d,J = 7.6 Hz, 1H), 7.22 (t,J = 7.6 Hz, 1H), 7.15 (d,J = 2.0 Hz, 1H), 7.02 (dd,J = 2.4, 8.8 Hz, 1H), 5.70 (q,J = 6.8 Hz, 1H), 4.03 (dd,J = 4.0, 8.0 Hz, 2H), 3.94 (d,J = 8.0 Hz, 2H), 2.61 (s, 3H), 2.57 (s, 3H), 1.63 - 1.59 (m, 6H)。LCMS [M+1]⁺ : 431.3。 10-48

(R )-1-(1-甲基-4-((1-(2-甲基-3-(三氟甲基)苯基)乙基)胺基)呔

-6-基)氮雜環丁烷-3-醇 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 14.61 (br s, 1H), 8.44 (br d,J = 6.4 Hz, 1H), 8.09 (d,J = 8.8 Hz, 1H), 7.77 (d,J = 8.0 Hz, 1H), 7.55 (d,J = 8.0 Hz, 1H), 7.46 (s, 1H), 7.34 (t,J = 7.6 Hz, 1H), 7.13 (dd,J = 2.0, 9.2 Hz, 1H), 5.96 (d,J = 6.0 Hz, 1H), 5.43 (br t,J = 6.8 Hz, 1H), 4.76 - 4.66 (m, 1H), 4.49 - 4.39 (m, 2H), 4.00 - 3.90 (m, 2H), 2.69 (s, 3H), 2.56 (s, 3H), 1.61 (d,J = 6.8 Hz, 3H)。 LCMS [M+1]⁺ : 417.1。 10-49

(R )-7-(4-(3,3-二氟吡咯啶-1-基)哌啶-1-基)-4-甲基-N -(1-(2-甲基-3-(三氟甲基)苯基)乙基)呔

-1-胺 甲酸鹽 ¹ H NMR (400 MHz, DMSO-d₆ ) δ = 8.16 (s, 1H), 7.80-7.74 (m, 2H), 7.62-7.54 (m, 2H), 7.51 (d,J = 7.6 Hz, 1H), 7.42 (d,J = 6.4 Hz, 1H), 7.31 (t,J = 7.6 Hz, 1H), 5.71 - 5.62 (m, 1H), 4.02 - 3.98 (m, 2H), 3.04 -2.96 (m, 5H), 2.80 (t,J = 7.2 Hz, 2H), 2.58 (s, 3H), 2.43-2.39 (m, 2H), 2.37 - 2.17 (m, 3H), 2.03 - 1.90 (m, 2H), 1.55 (d,J = 7.2 Hz, 3H), 1.54 - 1.45 (m, 2H)。LCMS [M+1]⁺ : 534.4。 10-50

(R )-N -(1-(3-氟-5-(三氟甲基)苯基)乙基)-4-甲基-7-

啉基呔

-1-胺 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 7.84 (d,J = 8.8 Hz, 1H), 7.64 (s, 1H), 7.55-7.62 (m, 3H), 7.48 (d,J = 10.4 Hz, 1H), 7.36 (d,J = 7.6 Hz, 1H), 5.50 - 5.54 (m, 1H), 3.84 - 3.82 (m, 4H), 3.42 - 3.44 (m, 4H), 2.55 (s, 3H), 1.61 (d,J = 7.2 Hz, 3H)。LCMS [M+1]⁺ : 435.2。 10-51

(R)-2-甲基-3-(1-((4-甲基-7-

啉基呔

-1-基)胺基)乙基)苯甲腈 ¹ H NMR (400 MHz, CD₃ OD) δ = 7.86 (d,J = 8.8 Hz, 1H), 7.77 - 7.68 (m, 1H), 7.58 - 7.52 (m, 2H), 7.46 (dd,J = 1.2, 7.6 Hz, 1H), 7.22 (t,J = 8.0 Hz, 1H), 5.61 (q,J = 7.2 Hz, 1H), 3.92 - 3.84 (m, 4H), 3.49 - 3.41 (m, 4H), 2.72 (s, 3H), 2.59 (s, 3H), 1.61 (d,J = 6.8 Hz, 3H)。LCMS [M+1]⁺ : 388.3。 10-52

(R )-3-氟-5-(1-((4-甲基-7-

啉基呔

-1-基)胺基)乙基)苯甲腈 ¹ H NMR (400 MHz, CD₃ OD) δ = 7.89 (d,J = 9.2 Hz, 1H), 7.63 (t,J = 1.2 Hz, 1H), 7.58 - 7.49 (m, 3H), 7.33 - 7.28 (m, 1H), 5.42 (q,J = 6.8 Hz, 1H), 3.89 - 3.84 (m, 4H), 3.46 - 3.40 (m, 4H), 2.62 (s, 3H), 1.66 (d,J = 7.2 Hz, 3H)。LCMS [M+1]⁺ : 392.2。 10-53

3-((1R )-1-((7-(6-氧雜-3-氮雜雙環[3.1.1]庚-3-基)-4-甲基呔

-1-基)胺基)乙基)-2-甲基苯甲腈 甲酸鹽 ¹ H NMR (400 MHz, CDCl₃ ) δ = 7.66 (t,J = 8.4 Hz, 2H), 7.48 - 7.36 (m, 2H), 7.28 - 7.25 (m, 2H), 7.15 (t,J = 7.6 Hz, 1H), 5.52 - 5.36 (m, 1H), 4.88 (d,J = 6.4 Hz, 2H), 3.92 - 3.73 (m, 4H), 3.49 - 3.35 (m, 1H), 2.72 (s, 3H), 2.57 (s, 3H), 2.01 (d,J = 9.2 Hz, 1H), 1.65 (d,J = 6.8 Hz, 3H)。LCMS [M+1]⁺ : 400.2。 10-54

3-((R )-1-((7-((1R ,4R )-2-氧雜-5-氮雜雙環[2.2.1]庚-5-基)-4-甲基呔

-1-基)胺基)乙基)-2-甲基苯甲腈 甲酸鹽 ¹ H NMR (400 MHz, CD₃ OD) δ = 8.55 (br s, 1H), 8.04 (d,J = 8.8 Hz, 1H), 7.72 (d,J = 7.6 Hz, 1H), 7.52 (d,J = 7.6 Hz, 1H), 7.44 - 7.34 (m, 2H), 7.27 (t,J = 8.4 Hz, 1H), 5.47 (q,J = 6.8 Hz, 1H), 4.98 (s, 1H), 4.82 (s, 1H), 3.97 (d,J = 7.2 Hz, 1H), 3.88 (d,J = 7.6 Hz, 1H), 3.72 (d,J = 10.4 Hz, 1H), 3.43 (d,J = 10.4 Hz, 1H), 2.73 (s, 3H), 2.69 (s, 3H), 2.11 (s, 2H), 1.64 (d,J = 7.2 Hz, 3H)。LCMS [M+1]⁺ : 400.2。 10-55

(R )-2-甲基-3-(1-((4-甲基-7-(哌

-1-基)呔

-1-基)胺基)乙基)苯甲腈 甲酸鹽 ¹ H NMR (400 MHz, CD₃ OD) δ = 8.49 (br s, 1H), 8.11 (d,J = 8.8 Hz, 1H), 7.79 - 7.69 (m, 3H), 7.52 (d,J = 7.2 Hz, 1H), 7.27 (t,J = 7.6 Hz, 1H), 5.50 (q,J = 6.8 Hz, 1H), 3.83 - 3.77 (m, 4H), 3.29 - 3.25 (m, 4H), 2.74 (s, 3H), 2.72 (s, 3H), 1.65 (d,J = 6.8 Hz, 3H)。LCMS [M+1]⁺ : 387.1。 10-56

3-((R )-1-((7-((S )-六氫吡

并[2,1-c ][1,4]

-8(1H )-基)-4-甲基呔

-1-基)胺基)乙基)-2-甲基苯甲腈 甲酸鹽 ¹ H NMR (400 MHz, CD₃ OD) δ = 8.53 (s, 1H), 7.98 (d,J = 8.8 Hz, 1H), 7.72 (d,J = 8.0 Hz, 1H), 7.67 - 7.59 (m, 2H), 7.50 (d,J = 7.6 Hz, 1H), 7.25 (t,J = 7.6 Hz, 1H), 5.59 - 5.49 (m, 1H), 4.14 (d,J = 11.6 Hz, 1H), 3.98 (d,J = 12.0 Hz, 1H), 3.93 - 3.83 (m, 2H), 3.78 - 3.68 (m, 1H), 3.37 (d,J = 10.8 Hz 1H), 3.16 (dt,J = 2.8, 12.0 Hz, 1H), 2.99 (br d,J = 11.6 Hz, 1H), 2.81 (d,J = 11.2 Hz 1H), 2.73 (s, 3H), 2.71 - 2.67 (m, 1H), 2.66 (s, 3H), 2.53 - 2.37 (m, 3H), 1.63 (d,J = 6.8 Hz, 3H)。LCMS [M+1]⁺ : 443.2。 10-57

(R )-3-(1-((7-(4-(二甲基胺基)哌啶-1-基)-4-甲基呔

-1-基)胺基)乙基)-2-甲基苯甲腈 甲酸鹽 ¹ H NMR (400 MHz, CD₃ OD) δ = 8.53 (br s, 1H), 8.03 (br d,J = 9.2 Hz, 1H), 7.76 - 7.62 (m, 3H), 7.52 (br d,J = 8.4 Hz, 1H), 7.27 (t,J = 7.6 Hz, 1H), 5.55 - 5.45 (m, 1H), 4.39 (br d,J = 12.8 Hz, 2H), 3.13 (t,J = 12.8 Hz, 2H), 3.03 - 2.94 (m, 1H), 2.73 (s, 3H), 2.68 (s, 3H), 2.62 - 2.54 (m, 6H), 2.16 (d,J = 11.6 H, 2H), 1.76 - 1.67 (m, 2H), 1.65 (d,J = 7.2 Hz, 3H)。LCMS [M+1]⁺ : 429.2。 10-58

(R )-3-(1-((7-(3-羥基-3-甲基氮雜環丁烷-1-基)-4-甲基呔

-1-基)胺基)乙基)-2-甲基苯甲腈 ¹ H NMR (400 MHz, CD₃ OD) δ = 8.10 (d,J = 8.8 Hz, 1H), 7.73 (d,J = 7.6 Hz, 1H), 7.55 - 7.51 (m, 1H), 7.34 - 7.26 (m, 2H), 7.16 (dd,J = 2.0, 9.2 Hz, 1H), 5.42 (d,J = 6.8 Hz, 1H), 4.20 - 4.16 (m, 2H), 4.14 - 4.08 (m, 2H), 2.74 (s, 3H), 2.73 (s, 3H), 1.66 (d,J = 7.2 Hz, 3H), 1.62 (s, 3H)。LCMS [M+1]⁺ : 388.2。 10-59

(R )-N -(1-(2-氯-4-氟苯基)乙基)-4-甲基-7-

啉基呔

-1-胺 鹽酸鹽 ¹ H NMR (400 MHz, DMSO-d₆ ) δ = 14.8 (s, 1H), 8.60 (d,J = 6.4 Hz, 1H), 8.17 (d,J = 9.2 Hz, 1H), 7.92 (d,J = 0.8 Hz, 1H), 7.77 (dd,J = 2.4, 9.6 Hz, 1H), 7.58 (dd,J = 6.4, 8.8 Hz, 1H), 7.44 (dd,J = 2.8, 8.8 Hz, 1H), 7.22 - 7.15 (m, 1H), 5.47 (m, 1H), 3.79 - 3.86 (m, 4H), 3.74 - 3.66 (m, 4H), 2.73 (s, 3H), 1.63 (d,J = 6.8 Hz, 3H)。LCMS [M+1]⁺ : 401.1。 10-60

N -(1-(2-氯-3-甲基苯基)乙基)-4-甲基-7-

啉基呔

-1-胺 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.18 (s, 1H), 8.09 - 8.07 (m, 1H), 7.80 - 7.79 (m, 1H), 7.74 - 7.71 (m, 1H), 7.32-7.31 (m, 1H), 7.23 - 7.21 (m, 1H), 7.18 - 7.14 (m, 1H), 5.61-5.54 (m, 1H), 3.85 - 3.82 (m, 4H), 3.63 - 3.62 (m, 4H), 2.66 (s, 3H), 2.37 (s, 3H), 1.62-1.61 (m, 3H)。LCMS [M+1]⁺ : 397.1。 10-61

(R )-4-甲基-N -(1-(3-甲基-5-(三氟甲基)苯基)乙基)-7-

啉基呔

-1-胺 ¹ H NMR (400 MHz, CD₃ OD) δ = 8.19 - 8.16 (m, 1H), 7.74 - 7.73 (m, 2H) 7.53 (s, 2H), 7.34 (s, 1H), 5.29 - 5.27 (m, 1H), 3.91 - 3.89 (m, 4H), 3.71 - 3.69 (m, 4H), 2.77 (s, 3H), 2.39 (s, 3H), 1.71 - 1.69 (m, 3H)。LCMS [M+1]⁺ : 431.1。 10-62

7-((S )-6-氟-1,4-二氮雜環庚烷-1-基)-4-甲基-N -((R )-1-(2-甲基-3-(三氟甲基)苯基)乙基)呔

-1-胺 鹽酸鹽 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 14.77 (s, 1H), 9.84 (s, 1H), 8.92 (s, 1H), 8.78 - 8.77 (m, 1H), 8.19 - 8.16 (m, 1H), 7.89 (s, 1H), 7.83 - 7.82 (m, 1H), 7.73 - 7.71 (m, 1H), 7.59 - 7.55 (m, 1H), 7.37 - 7.33 (m, 1H), 5.49 - 5.37 (m, 2H), 4.61 - 4.55 (m, 1H), 4.25 - 4.21 (m, 1H), 4.09 - 3.97 (m, 2H), 3.62 - 3.58 (m, 2H), 3.48 (s, 2H), 2.73 (s, 3H), 2.56 (s, 3H), 1.86 - 1.84 (m, 3H)。LCMS [M+1]⁺ : 462.1。 10-63

7-((R )-6-氟-1,4-二氮雜環庚烷-1-基)-4-甲基-N -((R )-1-(2-甲基-3-(三氟甲基)苯基)乙基)呔

-1-胺 鹽酸鹽 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 14.75 (s, 1H), 9.76 (s, 1H), 8.92 (s, 1H), 8.69 (s, 1H), 8.19 - 8.16 (m, 1H), 7.85 (s, 1H), 7.79 - 7.77 (m, 1H), 7.73 - 7.71 (m, 1H), 7.57 - 7.55 (m, 1H), 7.37 - 7.33 (m, 1H), 5.51 - 5.34 (m, 2H), 4.56 - 4.50 (m, 1H), 4.20 (s, 1H), 4.10 - 4.00 (m, 2H), 3.55 (s, 2H), 3.49 (s, 2H), 2.73 (s, 3H), 2.58 (s, 3H), 1.85 - 1.84 (m, 3H)。LCMS [M+1]⁺ : 462.1。 10-64

(R )-5-(1-甲基-4-((1-(2-甲基-3-(三氟甲基)苯基)乙基)胺基)呔

-6-基)-1,2,5-硫雜二氮雜環庚烷1,1-二氧化物 ¹ H NMR (400 MHz, 甲醇-d ₄ ) δ = 8.02 (d,J = 9.1 Hz, 1H), 7.69 (d,J = 7.8 Hz, 1H), 7.55 - 7.48 (m, 3H), 7.24 (t,J = 7.9 Hz, 1H), 5.64 (q,J = 6.9 Hz, 1H), 4.17 - 4.09 (m, 4H), 3.58 - 3.54 (m, 2H), 3.39 (t,J = 6.0 Hz, 2H), 2.66 (s, 3H), 2.61 (d,J = 1.6 Hz, 3H), 1.64 (d,J = 7.0 Hz, 3H)。LCMS [M+1]⁺ : 494.4 10-65

(R )-N -(1-(3-(二氟甲基)-2-甲基苯基)乙基)-4-甲基-7-

啉基呔

-1-胺 鹽酸鹽 ¹ H NMR (400 MHz, CD₃ OD) δ 8.16 (d,J = 9.3 Hz, 1H), 7.78 - 7.69 (m, 2H), 7.59 (d,J = 7.8 Hz, 1H), 7.38 (d,J = 7.6 Hz, 1H), 7.23 (t,J = 7.7 Hz, 1H), 6.94 (t,J = 55.3 Hz, 1H), 5.53 (q,J = 6.9 Hz, 1H), 4.61 (s, 3H), 3.93 - 3.87 (m, 4H), 3.73 - 3.64 (m, 4H), 2.75 (s, 3H), 2.56 (s, 3H), 1.66 (d,J = 6.9 Hz, 3H)。LCMS [M+1]⁺ : 413.2。 10-66

(R )-7-(3-(二甲基胺基)-3-甲基氮雜環丁烷-1-基)-4-甲基-N -(1-(2-甲基-3-(三氟甲基)苯基)乙基)呔

-1-胺 ¹ H NMR (400 MHz, CDCl₃ ) δ = 7.76 (d,J = 8.8 Hz, 1H), 7.67 (d,J = 7.8 Hz, 1H), 7.53 (d,J = 7.8 Hz, 1H), 7.25 - 7.19 (m, 1H), 6.90 (dd,J = 8.9, 2.2 Hz, 1H), 6.39 (d,J = 2.2 Hz, 1H), 5.85 (s, 1H), 4.88 (s, 1H), 3.87 (dd,J = 7.1, 3.5 Hz, 2H), 3.76 (dd,J = 7.1, 3.6 Hz, 2H), 2.68 (s, 3H), 2.56 (d,J = 1.7 Hz, 3H), 2.23 (s, 6H), 1.65 (d,J = 6.7 Hz, 3H), 1.39 (s, 3H)。LCMS [M+1]⁺ : 458.4。 10-67

(R )-3-(1-((7-(4,4-二氟哌啶-1-基)-4-甲基呔

-1-基)胺基)乙基)-2-甲基苯甲腈 ¹ H NMR (400 MHz, CD₃ OD) δ 7.96 (d,J = 9.1 Hz, 1H), 7.76 - 7.63 (m, 3H), 7.50 (dd,J = 7.7, 1.4 Hz, 1H), 7.25 (t,J = 7.8 Hz, 1H), 5.58 (q,J = 7.0 Hz, 1H), 3.75 (t,J = 5.8 Hz, 5H), 2.74 (s, 3H), 2.64 (s, 3H), 2.21 - 2.10 (m, 5H), 1.64 (d,J = 7.0 Hz, 3H)。LCMS [M+1]⁺ : 422.2。 10-68

(R )-3-(1-((7-(4-(氮雜環丁烷-1-基)哌啶-1-基)-4-甲基呔

-1-基)胺基)乙基)-2-甲基苯甲腈 ¹ H NMR (400 MHz, CD₃ OD) δ = 7.87 - 7.83 (m, 1H), 7.73 (dd,J = 8.0, 1.4 Hz, 1H), 7.57 - 7.53 (m, 2H), 7.48 (dd,J = 7.6, 1.3 Hz, 1H), 7.24 (t,J = 7.8 Hz, 1H), 5.62 (q,J = 6.9 Hz, 1H), 4.12 (d,J = 13.0 Hz, 2H), 2.98 (td,J = 12.7, 2.6 Hz, 2H), 2.74 (s, 3H), 2.59 (s, 3H), 2.45 - 2.34 (m, 1H), 2.12 (p,J = 7.1 Hz, 2H), 1.94 - 1.85 (m, 2H), 1.62 (d,J = 6.9 Hz, 3H), 1.37 (t,J = 12.1 Hz, 2H)。LCMS [M+1]⁺ : 441.2。 10-69

(R )-2-甲基-3-(1-((4-甲基-7-(6-甲基-5-側氧基-2,6-二氮雜螺[3.4]辛-2-基)呔

-1-基)胺基)乙基)苯甲腈 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.80 (d,J = 8.9 Hz, 1H), 7.74 (dd,J = 7.9, 1.4 Hz, 1H), 7.59 (dd,J = 7.6, 1.4 Hz, 1H), 7.30 (dd,J = 9.2, 6.6 Hz, 2H), 7.19 (d,J = 2.3 Hz, 1H), 7.01 (dd,J = 8.9, 2.2 Hz, 1H), 5.58 - 5.49 (m, 1H), 4.11 (t,J = 8.2 Hz, 2H), 4.00 (dd,J = 7.7, 4.3 Hz, 2H), 2.79 (s, 3H), 2.66 (s, 3H), 2.44 (t,J = 6.9 Hz, 2H), 1.53 (d,J = 7.0 Hz, 3H)。LCMS [M+1]⁺ : 441.4。 10-70

(R )-2-甲基-3-(1-((4-甲基-7-(4-(1-甲基-1H -吡唑-4-基)哌

-1-基)呔

-1-基)胺基)乙基)苯甲腈 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 7.81 (d,J = 8.9 Hz, 1H), 7.75 (dd,J = 8.0, 1.4 Hz, 1H), 7.65 - 7.57 (m, 3H), 7.41 (d,J = 6.8 Hz, 1H), 7.36 (s, 1H), 7.30 (t,J = 7.8 Hz, 1H), 7.25 (s, 1H), 5.56 (q,J = 6.7 Hz, 1H), 3.75 (s, 3H), 3.59 - 3.53 (m, 4H), 3.05 (t,J = 5.1 Hz, 4H), 2.67 (s, 3H), 2.53 (s, 3H), 1.55 (d,J = 6.9 Hz, 3H)。LCMS [M+1]⁺ : 467.2。 10-71

2-甲基-3-((R )-1-((4-甲基-7-((1R ,4R )-5-甲基-2,5-二氮雜雙環[2.2.2]辛-2-基)呔

-1-基)胺基)乙基)苯甲腈 ¹ H NMR (400 MHz, CDCl₃ ) δ = 7.77 (d,J = 9.2 Hz, 1H), 7.67 (d,J = 7.2 Hz, 1H), 7.45 (dd,J = 1.2, 7.6 Hz, 1H), 7.26 (s, 1H), 7.22 - 7.14 (m, 2H), 6.56 (d,J = 2.4 Hz, 1H), 5.73 (br t,J = 6.4 Hz, 1H), 4.95 (br d,J = 4.8 Hz, 1H), 4.03 (br s, 1H), 3.90 (m, 1H), 3.31 (m, 1H), 3.10 (m, 1H), 2.96 - 2.87 (m, 2H), 2.68 (d,J = 7.2 Hz, 6H), 2.47 (s, 3H), 2.24 - 2.13 (m, 1H), 2.07 - 1.96 (m, 1H), 1.93 (m, 1H), 1.61 (d,J = 6.4 Hz, 3H)。LCMS [M+1]⁺ : 427.2 10-72

(R )-4-甲基-N -(1-(2-甲基吡啶-3-基)乙基)-7-

啉基呔

-1-胺 ¹ H NMR (400 MHz, CD₃ OD) δ = 8.21 (dd,J = 1.6, 4.8 Hz, 1H), 7.90 (br d,J = 8.4 Hz, 1H), 7.85 (dd,J = 1.6, 7.6 Hz, 1H), 7.62 - 7.53 (m, 2H), 7.16 (dd,J = 1.6, 7.6 Hz, 1H), 5.59 (q,J = 6.8 Hz, 1H), 3.96 - 3.84 (m, 4H), 3.50 - 3.40 (m, 4H), 2.73 (s, 3H), 2.61 (s, 3H), 1.64 (d,J = 6.8 Hz, 3H)。LCMS [M+1]⁺ : 364.2。 10-73

(R )-2-甲基-3-(1-((4-甲基-7-(6-甲基-2,6-二氮雜螺[3.4]辛-2-基)呔

-1-基)胺基)乙基)苯甲腈 甲酸鹽 ¹ H NMR (400 MHz, CD₃ OD) δ = 8.55 (s, 1H), 8.01 (d,J = 9.2 Hz, 1H), 7.72 (d,J = 8.0 Hz, 1H), 7.55 - 7.50 (m, 1H), 7.30 - 7.26 (m, 1H), 7.25 (d,J = 2.0 Hz, 1H), 7.12 - 7.08 (m, 1H), 5.57 - 5.41 (m, 1H), 4.24 - 4.16 (m, 2H), 4.16 - 4.10 (m, 2H), 3.04 (s, 2H), 2.84 (t,J = 6.8 Hz, 2H), 2.74 (s, 3H), 2.68 (s, 3H), 2.52 (s, 3H), 2.32 (t,J = 6.8 Hz, 2H), 1.64 (d,J = 6.8 Hz, 3H)。LCMS [M+1]⁺ : 427.3。 10-74

(R )-3-(1-((7-(3-(二甲基胺基)-3-甲基氮雜環丁烷-1-基)-4-甲基呔

-1-基)胺基)乙基)-2-甲基苯甲腈 鹽酸鹽 ¹ H NMR (400 MHz, CD₃ OD) δ = 8.19 (d,J = 9.2 Hz, 1H), 7.79 (d,J = 7.2 Hz, 1H), 7.61 - 7.49 (m, 2H), 7.34 - 7.19 (m, 2H), 5.44 (q,J = 7.2 Hz, 1H), 4.56 (dd,J = 5.6, 9.6 Hz, 2H), 4.29 (dd,J = 6.0, 10.0 Hz, 2H), 2.94 (s, 6H), 2.76 (d,J = 9.6 Hz, 6H), 1.83 (s, 3H), 1.69 (d,J = 7.2 Hz, 3H)。LCMS [M+1]⁺ : 415.3。 10-75

(R )-3-(1-((7-(3-(二甲基胺基)氮雜環丁烷-1-基)-4-甲基呔

-1-基)胺基)乙基)-2-甲基苯甲腈 鹽酸鹽 ¹ H NMR (400 MHz, CD₃ OD) δ = 8.19 (d,J = 9.2 Hz, 1H), 7.79 (d,J = 8.0 Hz, 1H), 7.60 - 7.51 (m, 2H), 7.33 - 7.24 (m, 2H), 5.44 (q,J = 6.8 Hz, 1H), 4.67 - 4.57 (m, 2H), 4.51 (td,J = 5.2, 10.4 Hz, 2H), 4.47 - 4.38 (m, 1H), 3.01 (s, 6H), 2.76 (d,J = 7.2 Hz, 6H), 1.69 (d,J = 7.2 Hz, 3H)。LCMS [M+1]⁺ : 401.2。 10-76

(R )-7-(3-(二甲基胺基)氮雜環丁烷-1-基)-N -(1-(2-氟-3-(三氟甲基)苯基)乙基)-4-甲基呔

-1-胺 ¹ H NMR (400 MHz, DMSO-d ₆ ) : δ = 7.79 (d,J = 8.8 Hz, 1H), 7.71 (t,J = 6.8 Hz, 1H), 7.60 (t,J = 6.8 Hz, 1H), 7.33 - 7.22 (m, 2H), 7.20 (s, 1H), 7.08 - 6.93 (m, 1H), 5.73 - 5.70 (m, 1H), 4.21 - 4.04 (m, 2H), 3.90 - 3.70 (m, 2H), 3.29 - 3.27 (m, 1H), 2.52 - 2.51 (m, 3H), 2.16 (s, 6H), 1.61 (d,J = 6.8 Hz, 3H)。LCMS [M+1]⁺ : 448.3。 10-77

(R )-N -(1-(2-氟-3-(三氟甲基)苯基)乙基)-4-甲基-7-

啉基呔

-1-胺 ¹ H NMR (400 MHz, CD₃ OD) δ 7.91 (dd,J = 13.0, 8.8 Hz, 1H), 7.71 - 7.55 (m, 3H), 7.48 (d,J = 7.5 Hz, 1H), 7.18 (t,J = 7.9 Hz, 1H), 5.72 (q,J = 7.0 Hz, 1H), 3.97 - 3.88 (m, 4H), 3.53 - 3.45 (m, 4H), 2.62 - 2.57 (m, 3H), 1.69 (d,J = 7.0 Hz, 3H)。LCMS [M+1]⁺ : 435.2。 10-78

(R )-7-(3-(二甲基胺基)-3-甲基氮雜環丁烷-1-基)-N -(1-(2-氟-3-(三氟甲基)苯基)乙基)-4-甲基呔

-1-胺 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.79 (d,J = 8.9 Hz, 1H), 7.71 (t,J = 7.3 Hz, 1H), 7.60 (t,J = 7.3 Hz, 1H), 7.32 - 7.19 (m, 3H), 7.03 (dd,J = 8.8, 2.2 Hz, 1H), 3.83 - 3.74 (m, 4H), 3.29 (s, 3H), 2.15 (s, 6H), 1.61 (d,J = 7.1 Hz, 3H), 1.34 (s, 3H)。LCMS [M+1]⁺ : 462.1。 10-79

(R )-2-甲基-3-(1-((4-甲基-7-(5-甲基-8-氧雜-2,5-二氮雜螺[3.5]壬-2-基)呔

-1-基)胺基)乙基)苯甲腈 甲酸鹽 ¹ H NMR (400 MHz, CD₃ OD) δ = 7.99 (d,J = 9.0 Hz, 1H), 7.73 (dd,J = 7.9, 1.3 Hz, 1H), 7.50 (dt,J = 7.7, 1.3 Hz, 1H), 7.29 - 7.23 (m, 2H), 7.16 - 7.12 (m, 1H), 5.51 (q,J = 7.0 Hz, 1H), 4.32 (d,J = 9.4 Hz, 2H), 3.86 - 3.75 (m, 6H), 2.73 (s, 3H), 2.66 (s, 3H), 2.63 - 2.60 (m, 2H), 2.50 (s, 3H), 1.63 (d,J = 6.9 Hz, 3H)。LCMS [M+1]⁺ : 443.2。 10-80

(R )-2-甲基-3-(1-((4-甲基-7-(6-氧雜-2-氮雜螺[3.4]辛-2-基)呔

-1-基)胺基)乙基)苯甲腈 鹽酸鹽 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 14.65 (s, 1H), 8.47 (s, 1H), 8.11 (d,J = 9.0 Hz, 1H), 7.77 (d,J = 8.0 Hz, 1H), 7.64 (d,J = 7.5 Hz, 1H), 7.48 (s, 1H), 7.34 (t,J = 7.8 Hz, 1H), 7.18 - 7.11 (m, 1H), 5.37 - 5.29 (m, 1H), 4.25 - 4.15 (m, 4H), 3.91 - 3.86 (m, 2H), 3.78 (t,J = 6.9 Hz, 2H), 2.69 (s, 3H), 2.66 (s, 3H), 2.24 (t,J = 6.9 Hz, 2H), 1.60 (d,J = 7.0 Hz, 3H)。LCMS [M+1]⁺ : 414.2。 10-81

3-((R )-1-((7-((R )-六氫吡咯并[1,2-a ]吡

-2(1H )-基)-4-甲基呔

-1-基)胺基)乙基)-2-甲基苯甲腈 ¹ H NMR (400 MHz, CD₃ OD) δ 7.87 (d,J = 9.8 Hz, 1H), 7.73 (dd,J = 7.9, 1.4 Hz, 1H), 7.63 - 7.56 (m, 2H), 7.47 (d,J = 7.6 Hz, 1H), 7.23 (t,J = 7.8 Hz, 1H), 5.61 (q,J = 6.9 Hz, 1H), 4.20 (d,J = 11.9 Hz, 1H), 4.05 (d,J = 12.5 Hz, 1H), 3.26 - 3.02 (m, 3H), 2.73 (s, 3H), 2.59 (s, 3H), 2.45 (td,J = 11.4, 3.4 Hz, 1H), 2.28 (q,J = 9.1 Hz, 2H), 2.06 - 1.83 (m, 4H), 1.62 (d,J = 6.9 Hz, 3H), 1.60 - 1.51 (m, 1H)。LCMS [M+1]⁺ : 427.3。 10-82

2-甲基-3-((R )-1-((4-甲基-7-((R )-八氫-2H -吡啶并[1,2-a ]吡

-2-基)呔

-1-基)胺基)乙基)苯甲腈 鹽酸鹽 ¹ H NMR (400 MHz, 甲醇-d ₄ ) δ 8.25 (d,J = 9.3 Hz, 1H), 7.97 (d,J = 2.4 Hz, 1H), 7.89 - 7.77 (m, 2H), 7.56 (d,J = 7.6 Hz, 1H), 7.30 (t,J = 7.8 Hz, 1H), 5.47 (q,J = 7.0 Hz, 1H), 4.60 (t,J = 11.8 Hz, 2H), 3.67 (d,J = 12.5 Hz, 1H), 3.59 (t,J = 11.6 Hz, 2H), 3.49 - 3.35 (m, 1H), 3.33 - 3.26 (m, 1H), 3.18 - 3.07 (m, 1H), 2.80 (s, 3H), 2.76 (s, 3H), 2.21 - 2.13 (m, 1H), 2.05 - 2.00 (m, 3H), 2.00 - 1.92 (m, 1H), 1.84 - 1.68 (m, 5H)。LCMS [M+1]⁺ : 441.3。 10-83

(R )-2-甲基-3-(1-((4-甲基-7-(3-甲基-3-

啉基氮雜環丁烷-1-基)呔

-1-基)胺基)乙基)苯甲腈 甲酸鹽 ¹ H NMR (400 MHz, CD₃ OD) δ  = 8.55 (s, 1H), 8.02 (d,J = 9.0 Hz, 1H), 7.74 (dd,J = 7.9, 1.4 Hz, 1H), 7.52 (dd,J = 7.7, 1.4 Hz, 1H), 7.32 - 7.22 (m, 2H), 7.13 (dd,J = 9.0, 2.3 Hz, 1H), 5.50 (q,J = 6.9 Hz, 1H), 4.01 (t,J = 7.4 Hz, 2H), 3.88 (dd,J = 8.3, 5.9 Hz, 2H), 3.75 (t,J = 4.5 Hz, 3H), 2.72 (s, 3H), 2.69 (s, 3H), 2.59 - 2.54 (m, 4H), 1.64 (d,J = 7.0 Hz, 3H), 1.48 (s, 3H)。LCMS [M+1]⁺ : 457.3。 10-84

(R )-2-甲基-3-(1-((4-甲基-7-(5-甲基-2,5-二氮雜螺[3.4]辛-2-基)呔

-1-基)胺基)乙基)苯甲腈 ¹ H NMR (400 MHz, CD₃ OD) δ 7.88 (d,J = 8.9 Hz, 1H), 7.76 (dd,J = 7.9, 1.4 Hz, 1H), 7.51 (dd,J = 7.7, 1.4 Hz, 1H), 7.26 (t,J = 7.8 Hz, 1H), 7.18 (d,J = 2.3 Hz, 1H), 7.09 (dd,J = 8.9, 2.3 Hz, 1H), 5.63 (q,J = 6.9 Hz, 1H), 4.27 (dd,J = 8.5, 2.6 Hz, 2H), 3.92 (d,J = 8.5 Hz, 2H), 2.84 (t,J = 7.3 Hz, 2H), 2.76 (s, 3H), 2.61 (s, 3H), 2.54 (s, 3H), 2.28 - 2.20 (m, 2H), 1.96 - 1.84 (m, 2H), 1.64 (d,J = 6.9 Hz, 3H)。LCMS [M+1]⁺ : 427.3。 10-85

7-((1R ,4R )-2-氧雜-5-氮雜雙環[2.2.1]庚-5-基)-N-((R )-1-(3-(二氟甲基)-2-氟苯基)乙基)-4-甲基呔

-1-胺 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.78 (d,J = 9.0 Hz, 1H), 7.57 (t,J = 7.4 Hz, 1H), 7.45 (t,J = 7.1 Hz, 1H), 7.33 - 7.15 (m, 4H), 5.73 - 5.65 (m, 1H), 4.92 (s, 1H), 4.75 (s, 1H), 3.91 - 3.84 (m, 1H), 3.75 - 3.69 (m, 1H), 3.67 - 3.60 (m, 1H), 3.27 - 3.21 (m, 1H), 2.04 - 1.93 (m, 2H), 1.60 (d,J = 7.1 Hz, 3H), 1.24 (s, 1H)。LCMS [M+1]⁺ : 429.3。 10-86

N -((R )-1-(3-(二氟甲基)-2-氟苯基)乙基)-7-((S )-六氫吡

并[2,1-c ][1,4]

-8(1H )-基)-4-甲基呔

-1-胺 甲酸鹽 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.15 (s, 1H), 7.82 (d,J = 9.7 Hz, 1H), 7.64 - 7.54 (m, 2H), 7.46 (t,J = 7.1 Hz, 1H), 7.38 - 7.34 (m, 1H), 7.27 - 7.18 (m, 2H), 5.70 (t,J = 7.0 Hz, 1H), 4.12 - 4.04 (m, 1H), 3.92 - 3.77 (m, 3H), 3.64 - 3.53 (m, 1H), 3.27 - 3.20 (m, 1H), 3.03 - 2.90 (m, 2H), 2.78 - 2.71 (m, 1H), 2.70 - 2.67 (m, 1H), 2.54 (s, 3H), 2.42 - 2.34 (m, 1H), 2.32 - 2.22 (m, 2H), 1.62 (d,J = 7.1 Hz, 3H)。LCMS [M+1]⁺ : 472.4。 10-87

3-((R )-1-((7-((1R ,4R )-2-氧雜-5-氮雜雙環[2.2.1]庚-5-基)-4-甲基呔

-1-基)胺基)乙基)-2-(三氟甲基)苯甲腈 鹽酸鹽 ¹ H NMR (400 MHz, CD₃ OD) δ = 8.42 (d,J = 9.2 Hz, 1H), 8.37 (d,J = 8.0 Hz, 1H), 8.13 (d,J = 7.6 Hz, 1H), 7.98 (t,J = 7.9 Hz, 1H), 7.82 - 7.77 (m, 1H), 7.75 - 7.71 (m, 1H), 5.90 (q,J = 7.0 Hz, 1H), 5.37 (s, 1H), 5.14 (s, 1H), 4.30 (d,J = 7.6 Hz, 1H), 4.19 (d,J = 7.7 Hz, 1H), 4.08 - 4.01 (m, 1H), 3.80 (d,J = 10.5 Hz, 1H), 3.02 (s, 2H), 2.43 (d,J = 3.0 Hz, 3H), 2.03 (d,J = 6.9 Hz, 3H)。LCMS [M+1]⁺ : 454.2。 實例11-1(R )-(4-(1-甲基-4-((1-(2-甲基-3-(三氟甲基)苯基)乙基)胺基)呔

-6-基)哌

-1-基)(氧雜環丁烷-3-基)甲酮

Following the teaching of general reaction scheme III and the methods of preparing examples 10-1 and 10-2, the following compounds of formula (I) as shown in Table 10, examples 10-3 to 10-87 were prepared. Table 10 Example # structure Spectral data 10-3

4-(1-methyl-4-((( R )-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)

-6-yl)piperidin-2-one ¹ H NMR (400 MHz, CD ₃ OD) δ 8.70 (s, 1H), 8.39 (d, J = 8.5 Hz, 1H), 8.17 (dd, J = 8.5, 1.6 Hz, 1H), 7.74 (d, J = 7.9 Hz, 1H), 7.56 (s, 1H), 7.31 (s, 1H), 5.63-5.55 (m, 1H), 3.59-3.49 (m, 2H), 2.89 (s, 3H), 2.77-2.68 ( m, 2H), 2.66 (s, 3H), 2.29-2.22 (m, 3H), 1.73 (d, J = 6.9 Hz, 3H). LCMS [M+1] ⁺ : 443.2 10-4

( R ) -N -(1-(3-(Difluoromethyl)-2-methylphenyl)ethyl)-4-methyl-7-(piper

-1-base) 呔

-1-amine ¹ H NMR (400 MHz, CD ₃ OD) δ = 8.25 (d, J = 9.2 Hz, 1H), 7.96 (s, 1H), 7.83 (dd, J = 2.4, 9.2 Hz, 1H), 7.65 (d, J = 8.0 Hz, 1H), 7.40 (br d, J = 7.2 Hz, 1H), 7.30-7.20 (m, 1H), 7.13-6.80 (m, 1H), 5.6 (q, J = 6.8 Hz, 1H) , 4.17-3.93 (m, 4H), 3.58-3.43 (m, 4H), 2.80 (s, 3H), 2.59 (s, 3H), 1.71 (br d, J = 6.8 Hz, 3H). LCMS [M+1] ⁺ = 412.3. 10-5

( R )-7-(6,6-Difluoro-1,4-diazepan-1-yl)-4-methyl- N -(1-(2-methyl-3-(three (Fluoromethyl)phenyl)ethyl)

-1-amine ¹ H NMR (400 MHz, CD ₃ OD) δ = 7.89 (d, J = 8.8 Hz, 1H), 7.69 (d, J = 7.6 Hz, 1H), 7.56 (s, 1H), 7.53 (dd, J = 4.8, 8.8 Hz, 1H), 7.48 (d, J = 7.6 Hz, 1H), 7.22 (t, J = 8.0 Hz, 1H), 5.71 (br d, J = 6.8 Hz, 1H), 4.27 (dt, J = 2.0, 12.0 Hz, 2H), 3.89 (q, J = 4.8 Hz, 2H), 3.13 (t, J = 5.6 Hz, 2H), 3.07 (dt, J = 1.2, 14.8 Hz, 2H), 2.61 (s , 3H), 2.59 (s, 3H), 1.63 (d, J = 6.8 Hz, 3H). LCMS [M+1] ⁺ : 480.1. 10-6

4-methyl- N -(( R )-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-7-(( S )-3-methyl

Linyl)

-1-amine ¹ H NMR (400 MHz, CD ₃ OD) δ = 8.16 (d, J = 10.0 Hz, 1H), 7.74-7.65 (m, 3H), 7.53 (br d, J = 7.8 Hz, 1H), 7.28 (s , 1H), 5.53 (d, J = 6.8 Hz, 1H), 5.49 (s, 1H), 4.46-4.36 (m, 1H), 4.12 (dd, J = 3.6, 11.2 Hz, 1H), 3.95-3.81 ( m, 3H), 3.72 (dt, J = 2.8, 12.0 Hz, 1H), 3.51-3.40 (m, 1H), 3.35 (s, 1H), 2.75 (s, 3H), 2.63 (s, 3H), 1.66 (d, J = 6.8 Hz, 3H), 1.36 (d, J = 7.2 Hz, 3H). LCMS [M+1] ⁺ = 445.2. 10-7

(R)-4-methyl-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-7-(4-(methylamino)piperidine-1 -Base) eh

-1-amine ¹ H NMR (400 MHz, CD ₃ OD) δ = 8.16 (d, J = 9.6 Hz, 1H), 7.84 (s, 1H), 7.78-7.71 (m, 2H), 7.52 (d, J = 7.6 Hz, 1H), 7.27 (t, J = 16.0 Hz, 1H), 5.55-5.50 (m, 1H), 4.54 (d, J = 13.6 Hz, 2H), 3.51-3.31 (m, 1H), 3.28-3.23 (m , 2H), 2.78 (s, 3H), 2.75 (s, 3H), 2.62 (s, 3H), 2.31 (d, J = 10.8 Hz, 2H), 1.78-1.72 (m, 2H), 1.68 (d, J = 7.6 Hz, 3H). LCMS [M+1] ⁺ : 458.2. 10-8

( R )-7-(4-(dimethylamino)piperidin-1-yl)-4-methyl- N -(1-(2-methyl-3-(trifluoromethyl)phenyl )Ethyl) 呔

-1-amine ¹ H NMR (400MHz, CD ₃ OD) δ = 8.17 (d, J = 9.6 Hz, 1H), 7.85 (s, 1H), 7.78-7.72 (m, 2H), 7.52 (d, J = 8.0 Hz, 1H ), 7.27 (t, J = 8.0 Hz, 1H), 5.56-5.50 (m, 1H), 4.60 (d, J = 13.2 Hz, 2H), 3.66-3.63 (m, 1H), 3.30-3.22 (m, 2H), 2.93 (s, 6H), 2.75 (s, 3H), 2.32 (d, J = 9.6 Hz, 2H), 1.91-1.85 (m, 2H), 1.68 (d, J = 6.8 Hz, 3H). LCMS [M+1] ⁺ : 472.2. 10-9

( R )-7-(4-amino-4-methylpiperidin-1-yl)-4-methyl- N -(1-(2-methyl-3-(trifluoromethyl)phenyl )Ethyl) 呔

-1-amine ¹ H NMR (400 MHz, CD ₃ OD) δ 8.17 (d, J = 9.3 Hz, 1H), 7.85 (s, 1H), 7.79-7.71 (m, 2H), 7.53 (d, J = 7.8 Hz, 1H ), 7.27 (t, J = 7.8 Hz, 1H), 5.54 (q, J = 6.9 Hz, 1H), 4.21 (d, J = 14.1 Hz, 2H), 3.58 (dd, J = 14.1, 6.9 Hz, 2H ), 2.75 (s, 3H), 2.63 (s, 3H), 2.05-1.97 (m, 4H), 1.68 (d, J = 6.9 Hz, 3H), 1.57 (s, 3H). LCMS [M+1] ⁺ : 458.2. 10-10

(R)-4-methyl-7-(4-(1-methyl-1H-pyrazol-4-yl)piper

-1-yl)-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)

-1-amine ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 14.83 (s, 1H), 8.76 (s, 1H), 8.16 (d, J = 9.3 Hz, 1H), 8.03 (s, 1H), 7.85-7.79 ( m, 2H), 7.56 (d, J = 7.1 Hz, 2H), 7.36 (dd, J = 16.0, 8.2 Hz, 2H), 5.48 (q, J = 6.9 Hz, 1H), 3.92 (s, 4H), 3.78 (s, 3H), 3.17 (s, 5H), 2.73 (s, 3H), 2.59-2.56 (m, 3H), 1.64 (d, J = 6.9 Hz, 3H). LCMS [M+1] ⁺ : 510.2 10-11

( R )-7-(1,3-Dimethyl-5,6-dihydroimidazo[1,5-a]pyridine

-7(8 H )-yl)-4-methyl- N -(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)

-1-amine ¹ H NMR (400 MHz, CD ₃ OD) δ 8.30 (d, J = 9.3 Hz, 1H), 8.02 (d, J = 2.4 Hz, 1H), 7.92 (dd, J = 9.3, 2.5 Hz, 1H), 7.83 (d, J = 7.9 Hz, 1H), 7.57 (d, J = 7.8 Hz, 1H), 7.31 (t, J = 7.9 Hz, 1H), 5.61 (q, J = 6.9 Hz, 1H), 5.02 ( d, J = 2.5 Hz, 2H), 4.43 (t, J = 5.4 Hz, 2H), 4.30 (t, J = 5.4 Hz, 2H), 2.83 (s, 3H), 2.69-2.65 (m, 6H), 2.43 (s, 3H), 1.76 (d, J = 7.0 Hz, 3H). LCMS [M+1] ⁺ : 495.2. 10-12

( R )-2-(1-methyl-4-((( R )-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)

-6-yl)hexahydropyrrolo[1,2- a ]pyridine

-6(2 H )-ketone ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 7.80 (d, J = 8.8 Hz, 1H), 7.75 (d, J = 7.6 Hz, 1H), 7.65-7.63 (m, 2H), 7.50 (d , J = 7.6 Hz, 1H), 7.36 (d, J = 6.8 Hz, 1H), 7.30 (t, J = 8.0 Hz, 1H), 5.70-5.66 (m, 1H), 4.24-4.23 (m, 1H) , 4.12-3.96 (m, 1H), 3.94-3.93 (m, 1H), 3.72-3.71 (m, 1H), 3.09-3.20 (m, 1H), 2.91-3.02 (m, 1H), 2.60-2.71 ( m, 1H), 2.57 (s, 3H), 2.52 (s, 3H), 2.32-2.28 (m, 2H), 2.26-2.14 (m, 1H), 1.70-1.68 (m, 1H), 1.55 (d, J = 6.8 Hz, 3H). LCMS [M+1] ⁺ : 484.1. 10-13

( S )-2-(1-methyl-4-((( R )-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)

-6-yl)hexahydropyrrolo[1,2- a ]pyridine

-6(2 H )-ketone ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 7.80 (d, J = 8.8 Hz, 1H), 7.73 (d, J = 8.0 Hz, 1H), 7.64-7.60 (m, 2H), 7.50 (d , J = 7.6 Hz, 1H), 7.29 (t, J = 8.0 Hz, 1H), 5.68-5.63 (m, 1H), 4.22 (d, J = 10.4 Hz, 1H), 4.13 (d, J = 12.4 Hz , 1H), 4.09-3.95 (m, 1H), 3.72-3.71 (m, 1H), 2.97 (t, J = 9.2 Hz, 1H), 2.81 (t, J = 12.0 Hz, 1H), 2.67-2.61 ( m, 1H), 2.56 (s, 3H), 2.51 (s, 3H), 2.32-2.29 (m, 2H), 2.26-2.14 (m, 1H), 1.70-1.68 (m, 1H), 1.53 (d, J = 7.2 Hz, 3H). LCMS [M+1] ⁺ : 484.1. 10-14

(R)-7-(3,5-Dimethyl-1H-pyrazol-1-yl)-4-methyl-N-(1-(2-methyl-3-(trifluoromethyl)benzene (Base) ethyl) 呔

-1-amine ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 9.01 (brs, 1H), 8.95 (s, 1H), 8.47 (d, J = 8.8 Hz, 1H), 8.31 (d, J = 8.0 Hz, 1H ), 7.77 (d, J = 7.6 Hz, 1H), 7.58 (d, J = 8.0 Hz, 1H), 7.37 (m, 1H), 6.3 (s, 1H), 5.51(m, 1H), 2.84 (s , 3H), 2.58 (s, 3H), 2.49 (s, 3H), 2.28 (s, 3H), 1.63 (d, J = 6.8 Hz, 3H). LCMS [M+H] ⁺ : 440.6. 10-15

( R )-7-(5,6-Dihydropyrrolo[3,4- c ]pyrazole-1(4 H )-yl)-4-methyl- N -(1-(2-methyl- 3-(trifluoromethyl)phenyl)ethyl)

-1-amine ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 8.77-8.71 (m, 1H), 8.13-8.08 (m, 1H), 8.03-7.98 (m, 1H), 7.93 (br d, J = 6.4 Hz , 1H), 7.79 (d, J = 8.0 Hz, 1H), 7.70 (s, 1H), 7.51 (d, J = 7.6 Hz, 1H), 7.30 (t, J = 6.8 Hz, 1H), 5.74-5.63 (m, 1H), 4.66-4.52 (m, 2H), 4.15-4.05 (m, 2H), 2.64 (s, 3H), 2.59 (br s, 3H), 1.56 (d, J = 6.8 Hz, 3H) . LCMS [M+1] ⁺ : 453.3. 10-16

( R )-7-(5,6-Dihydropyrrolo[3,4- c ]pyrazole-2(4 H )-yl)-4-methyl- N -(1-(2-methyl- 3-(trifluoromethyl)phenyl)ethyl)

-1-amine ¹ H NMR (400 MHz, CD ₃ OD) δ = 8.75 (d, J = 2.0 Hz, 1H), 8.42-8.34 (m, 2H), 8.17 (d, J = 8.8 Hz, 1H), 7.75 (d, J = 8.0 Hz, 1H), 7.50 (d, J = 7.6 Hz, 1H), 7.25 (t, J = 8.0 Hz, 1H), 5.74 (q, J = 6.8 Hz, 1H), 4.42 (d, J = 7.2 Hz, 4H), 2.71 (s, 3H), 2.64 (s, 3H), 1.66 (d, J = 6.8 Hz, 3H). LCMS [M+1] ⁺ : 453.4. 10-17

( R )-4-methyl- N -(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-7-(1 H -pyrazol-1-yl)

-1-amine ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 9.20 (s, 1H), 8.98 (br s, 1H), 8.87 (d, J = 2.8 Hz, 1H), 8.65 (dd, J = 9.2 Hz, J = 2.0 Hz 1H), 8.51 (d, J = 8.8 Hz, 1H), 8.03 (d, J = 1.6 Hz, 1H), 7.81 (d, J = 7.6 Hz, 1H), 7.59 (d, J = 7.6 Hz, 1H), 7.38 (m, 1H), 6.81 (m, 1H), 5.52 (m, 1H), 2.83 (s, 3H), 2.59 (s, 3H), 1.66 (d, J = 6.8 Hz, 3H ). LCMS [M+H] ⁺ : 412.3. 10-18

( R )-4-methyl- N -(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-7-(1,8-diazaspiro[4.5]deca -8-base) 呔

-1-amine ¹ H NMR (400 MHz, CD ₃ OD) δ = 8.18 (d, J = 9.2 Hz, 1H), 7.89 (d, J = 2.4 Hz, 1H), 7.82-7.74 (m, 2H), 7.54 (d, J = 8.0 Hz, 1H), 7.29 (t, J = 7.6 Hz, 1H), 5.55 (q, J = 7.2 Hz, 1H), 4.28-4.16 (m, 2H), 3.70-3.57 (m, 2H), 3.47 (t, J = 6.8 Hz, 2H), 2.77 (s, 3H), 2.65 (s, 3H), 2.32-2.17 (m, 4H), 2.17-2.06 (m, 4H), 1.71 (d, J = 7.2 Hz, 3H). LCMS [M+1] ⁺ : 484.2. 10-19

( R )-4-methyl- N -(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-7-(1-methyl-1,8-diazepine Spiro[4.5]dec-8-yl) 呔

-1-amine ¹ H NMR (400 MHz, CD ₃ OD) δ = 8.19 (d, J = 9.2 Hz, 1H), 7.91 (d, J = 2.0 Hz, 1H), 7.84-7.74 (m, 2H), 7.54 (d, J = 8.0 Hz, 1H), 7.29 (t, J = 7.6 Hz, 1H), 5.56 (q, J = 6.8 Hz, 1H), 4.62-4.50 (m, 2H), 3.83-3.71 (m, 1H), 3.42-3.33 (m, 3H), 2.85 (s, 3H), 2.77 (s, 3H), 2.65 (s, 3H), 2.62-2.53 (m, 1H), 2.35-2.14 (m, 4H), 2.13- 1.93 (m, 3H), 1.71 (d, J = 7.2 Hz, 3H). LCMS [M+1] ⁺ : 498.3. 10-20

( R ) -N -(1-(2,4-Dichlorophenyl)ethyl)-4-methyl-7-

Linyl

-1-amine ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 7.82 (d, J = 9.2 Hz, 1H), 7.63-7.62 (m, 1H), 7.57-7.56 (m, 2H), 7.44 (d, J = 8.0 Hz, 1H), 7.41-7.39 (m, 1H), 7.32-7.31 (m, 1H), 5.64-5.60 (m, 1H), 3.82 (t, J = 4.8 Hz, 4H), 3.41 (t, J = 4.4 Hz, 4H), 2.52 (s, 3H), 1.55 (d, J = 7.2 Hz, 3H). LCMS [M+1] ⁺ : 417.0. 10-21

( R ) -N -(1-(2,4-Dichlorophenyl)ethyl)-4-methyl-7-(piper

-1-base) 呔

-1-amine ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 14.96 (s, 1H), 9.60 (s, 2H), 9.05 (s, 1H), 8.22-8.21 (m, 2H), 7.82-7.77 (m, 1H), 7.65 (d, J = 8.4 Hz, 1H), 7.60 (d, J = 2.4 Hz, 1H), 7.37 (dd, J = 2.0 Hz, 8.4 Hz, 1H), 5.50-5.43 (m, 1H) , 4.07-3.98 (m, 4H), 3.33-3.28 (m, 4H), 2.74 (s, 3H), 1.66 (d, J = 6.8 Hz, 3H). LCMS [M+1] ⁺ : 416.1. 10-22

7-(6-Fluoro-1,4-diazepan-1-yl)-4-methyl- N -(( R )-1-(2-methyl-3-(trifluoromethyl) )Phenyl) ethyl) 呔

-1-amine ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 7.88 (d, J = 9.2 Hz, 1H), 7.69 (d, J = 7.6 Hz, 1H), 7.51-7.47 (m, 3H), 7.22 (t , J = 8.0 Hz, 1H), 5.71-5.68 (m, 1H), 5.14-4.94 (m, 1H), 4.13-4.07 (m, 2H), 3.85-3.83 (m, 2H), 3.30-2.99 (m , 4H), 2.61-2.55 (m, 6H), 1.61 (d, J = 6.8 Hz, 3H). LCMS [M+1] ⁺ : 462.2. 10-23

( R )-4-(1-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)

-6-based) sulfur

Morpholino 1,1-dioxide ¹ H NMR (400 MHz, CD ₃ OD) δ = 7.95 (d, J = 8.8 Hz, 1H), 7.73-7.68 (m, 2H), 7.64 (dd, J = 2.4, 8.8 Hz, 1H), 7.48 ( d, J = 7.6 Hz, 1H), 7.23 (t, J = 7.6 Hz, 1H), 5.72 (q, J = 6.8 Hz, 1H), 4.20-4.11 (m, 4H), 3.25-3.17 (m, 4H ), 2.61 (s, 6H), 1.63 (d, J = 7.2 Hz, 3H). LCMS [M+1] ⁺ : 479.2. 10-24

4-methyl- N -(( R )-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-7-((( S )-1-methylpyrrolidine- 2-yl) methoxy) 呔

-1-amine hydrochloride ¹ H NMR (400 MHz, CD ₃ OD) δ = 8.40-8.36 (m, 2H), 7.88-7.77 (m, 2H), 7.54 (d, J = 8.0 Hz, 1H), 7.28 (t, J = 8.0 Hz, 1H), 5.58 (q, J = 6.8 Hz, 1H), 4.69 (br dd, J = 7.2, 11.2 Hz, 2H), 4.08 (br d, J = 3.6 Hz, 1H), 3.81 (br s, 1H), 3.15 (s, 3H), 2.86 (s, 3H), 2.64 (s, 3H), 2.51 (br dd, J = 6.0, 12.4 Hz, 1H), 2.45-2.04 (m, 4H), 1.73 ( d, J = 6.8 Hz, 3H). LCMS [M+1] ⁺ : 459.2. 10-25

4-methyl- N -(( R )-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-7-((( R )-1-methylpyrrolidine- 2-yl) methoxy) 呔

-1-amine hydrochloride ¹ H NMR (400 MHz, CD ₃ OD) δ = 8.48-8.29 (m, 2H), 7.89-7.79 (m, 2H), 7.56 (br d, J = 7.6 Hz, 1H), 7.30 (br t, J = 8.0 Hz, 1H), 5.63-5.54 (m, 1H), 4.85-4.67 (m, 3H), 4.15-4.05 (m, 1H), 3.89-3.79 (m, 1H), 3.17 (s, 3H), 2.88 (s, 3H), 2.66 (s, 3H), 2.60-2.44 (m, 1H), 2.36-2.10 (m, 3H), 1.74 (br d, J = 6.8 Hz, 3H). LCMS [M+1] ⁺ : 459.2. 10-26

7-(( R )-3-(dimethylamino)pyrrolidin-1-yl)-4-methyl- N -(( R )-1-(2-methyl-3-(trifluoromethyl) (Phenyl) Ethyl) Ethyl)

-1-amine hydrochloride ¹ H NMR (400 MHz, CD ₃ OD) δ = 8.22 (d, J = 9.2 Hz, 1H), 7.79 (d, J = 7.6 Hz, 1H), 7.60 (d, J = 2.0 Hz, 1H), 7.54 (d, J = 8.0 Hz, 1H), 7.49 (dd, J = 2.4, 9.2 Hz, 1H), 7.29 (t, J = 8.0 Hz, 1H), 5.57 (q, J = 6.8 Hz, 1H), 4.26 -4.17 (m, 2H), 4.06-3.96 (m, 1H), 3.95-3.85 (m, 1H), 3.78-3.67 (m, 1H), 3.09 (br d, J = 10.4 Hz, 6H), 2.78 ( s, 3H), 2.77-2.70 (m, 1H), 2.65 (s, 3H), 2.47 (qd, J = 8.4, 12.4 Hz, 1H), 1.72 (d, J = 6.8 Hz, 3H). LCMS [M+1] ⁺ : 458.2. 10-27

7-(( S )-3-(dimethylamino)pyrrolidin-1-yl)-4-methyl- N -(( R )-1-(2-methyl-3-(trifluoromethyl) (Phenyl) Ethyl) Ethyl)

-1-amine hydrochloride ¹ H NMR (400 MHz, CD ₃ OD) δ = 8.20 (d, J = 9.2 Hz, 1H), 7.77 (d, J = 7.6 Hz, 1H), 7.59 (d, J = 1.6 Hz, 1H), 7.52 (br d, J = 8.0 Hz, 1H), 7.47 (dd, J = 2.4, 9.2 Hz, 1H), 7.27 (t, J = 7.6 Hz, 1H), 5.55 (q, J = 6.8 Hz, 1H), 4.27-4.12 (m, 2H), 4.01-3.88 (m, 2H), 3.77-3.67 (m, 1H), 3.07 (br s, 6H), 2.76 (s, 3H), 2.74-2.69 (m, 1H) , 2.63 (s, 3H), 2.46 (qd, J = 8.8, 12.8 Hz, 1H), 1.70 (d, J = 7.2 Hz, 3H). LCMS[M+1] ⁺ : 458.3. 10-28

4-methyl- N -(( R )-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-7-(3-methyl-3,8-diazepine Bicyclo[3.2.1]oct-8-yl)

-1-amine hydrochloride ¹ H NMR (400 MHz, CD ₃ OD) δ = 8.25 (d, J = 9.2 Hz, 1H), 7.94 (d, J = 2.4 Hz, 1H), 7.80 (d, J = 8.0 Hz, 1H), 7.74 (dd, J = 2.4, 9.2 Hz, 1H), 7.54 (d, J = 7.6 Hz, 1H), 7.29 (t, J = 7.6 Hz, 1H), 5.56 (q, J = 6.8 Hz, 1H), 5.07 (br s, 2H), 3.60 (br d, J = 12.8 Hz, 2H), 3.40-3.34 (m, 2H), 2.87 (s, 3H), 2.79 (s, 3H), 2.65 (s, 3H), 2.47-2.24 (m, 4H), 1.72 (d, J = 6.8 Hz, 3H). LCMS [M+1] ⁺ : 470.2. 10-29

4-methyl- N -(( R )-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-7-(8-methyl-3,8-diazepine Bicyclo[3.2.1]oct-3-yl)

-1-amine hydrochloride ¹ H NMR (400 MHz, CD ₃ OD): δ = 8.28-8.21 (m, 1H), 7.94-7.90 (m, 1H), 7.81-7.73 (m, 2H), 7.55-7.50 (m, 1H), 7.31-7.24 (m, 1H), 5.60-5.51 (m, 1H), 4.43-4.32 (m, 2H), 4.28-4.21 (m, 2H), 3.84-3.58 (m, 2H), 3.01-2.91 (m , 3H), 2.83-2.76 (m, 3H), 2.65-2.60 (m, 3H), 2.49-2.33 (m, 2H), 2.25-2.12 (m, 2H), 1.74-1.66 (m, 3H). LCMS [M+1] ⁺ : 470.3. 10-30

( R )-7-(4-(azetidin-1-yl)piperidin-1-yl)-4-methyl- N -(1-(2-methyl-3-(trifluoromethyl (Phenyl) Ethyl) Ethyl)

-1-amine hydrochloride ¹ H NMR (400 MHz, CD ₃ OD) δ = 8.17 (d, J = 9.6 Hz, 1H), 7.86 (d, J = 2.4 Hz, 1H), 7.81-7.72 (m, 2H), 7.54 (d, J = 7.6 Hz, 1H), 7.34-7.25 (m, 1H), 5.55 (q, J = 7.2 Hz, 1H), 4.54 (br d, J = 13.6 Hz, 2H), 4.39-4.13 (m, 4H) , 3.65 (tt, J = 4.0, 11.2 Hz, 1H), 3.27 (br t, J = 12.4 Hz, 2H), 2.77 (s, 3H), 2.65 (s, 4H), 2.54-2.34 (m, 1H) , 2.24 (br d, J = 11.6 Hz, 2H), 1.70 (d, J = 6.8 Hz, 3H), 1.67-1.52 (m, 2H). LCMS [M+1] ⁺ : 484.3. 10-31

4-methyl- N -(( R )-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-7-((1 S ,4 S )-5-methyl -2,5-diazabicyclo[2.2.2]oct-2-yl)

-1-amine ¹ H NMR (400 MHz, CD ₃ OD) δ = 8.04 (d, J = 9.2 Hz, 1H), 7.70 (d, J = 8.0 Hz, 1H), 7.51 (d, J = 7.6 Hz, 1H), 7.48 -7.42 (m, 2H), 7.26 (t, J = 8.0 Hz, 1H), 5.57 (q, J = 6.8 Hz, 1H), 4.44 (br s, 1H), 4.02 (td, J = 2.4, 11.6 Hz , 1H), 3.52 (dd, J = 2.0, 11.6 Hz, 1H), 3.16-3.02 (m, 3H), 2.68 (s, 3H), 2.62 (s, 3H), 2.54 (s, 3H), 2.33- 2.20 (m, 1H), 2.13-1.92 (m, 2H), 1.84-1.73 (m, 1H), 1.65 (d, J = 6.8 Hz, 3H). LCMS [M+1] ⁺ : 470.2. 10-32

4-methyl- N -(( R )-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-7-((1 R ,4 R )-5-methyl -2,5-diazabicyclo[2.2.2]oct-2-yl)

-1-amine ¹ H NMR (400 MHz, CD ₃ OD) δ = 7.85 (d, J = 8.8 Hz, 1H), 7.70 (d, J = 7.6 Hz, 1H), 7.47 (d, J = 7.6 Hz, 1H), 7.33 (dd, J = 2.4, 8.8 Hz, 1H), 7.28 (d, J = 2.4 Hz, 1H), 7.22 (t, J = 8.0 Hz, 1H), 5.71 (q, J = 6.8 Hz, 1H), 4.30 (br s, 1H), 3.96 (td, J = 2.4, 10.8 Hz, 1H), 3.43 (dd, J = 2.0, 10.8 Hz, 1H), 3.11-2.94 (m, 3H), 2.61 (s, 3H) , 2.57 (s, 3H), 2.49 (s, 3H), 2.28-2.16 (m, 1H), 2.10-1.99 (m, 1H), 1.97-1.87 (m, 1H), 1.81-1.69 (m, 1H) , 1.62 (d, J = 6.8 Hz, 3H). LCMS [M+1] ⁺ : 470.2. 10-33

( R )-4-methyl- N -(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-7-(4-methyl-4,7-diazepine Spiro[2.5]oct-7-yl)

-1-amine ¹ H NMR (400 MHz, CD ₃ OD) δ = 7.88 (d, J = 8.8 Hz, 1H), 7.69 (d, J = 7.6 Hz, 1H), 7.58-7.52 (m, 2H), 7.47 (d, J = 7.6 Hz, 1H), 7.22 (t, J = 8.0 Hz, 1H), 5.72 (q, J = 6.8 Hz, 1H), 3.54 (dd, J = 4.8, 6.8 Hz, 2H), 3.35 (s, 2H), 3.18-3.11 (m, 2H), 2.64-2.57 (m, 6H), 2.48 (s, 3H), 1.62 (d, J = 6.8 Hz, 3H), 0.86-0.80 (m, 2H), 0.73 -0.64 (m, 2H).LCMS [M+1] ⁺ : 470.3. 10-34

( R )-4-methyl- N -(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-7-(4,7-diazaspiro[2.5]octane -7-base)

-1-amine ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 8.46 (br s, 1H), 8.06 (d, J = 9.2 Hz, 1H), 7.90 (br s, 1H), 7.81 (br d, J = 7.6 Hz, 1H), 7.72 (br d, J = 8.0 Hz, 1H), 7.54 (d, J = 7.6 Hz, 1H), 7.34 (br t, J = 8.0 Hz, 1H), 5.51 (br t, J = 6.8 Hz, 1H), 3.84 (br d, J = 4.8 Hz, 2H), 3.73 (br s, 2H), 3.25 (br s, 2H), 2.67 (s, 3H), 2.57 (s, 3H), 1.62 (br d, J = 6.8 Hz, 3H), 0.95-0.79 (m, 4H). LCMS [M+1] ⁺ : 456.2. 10-35

( R )-4-methyl- N -(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-7-(1,8-diazaspiro[4.5]deca -8-base) 呔

-1-amine ¹ H NMR (400 MHz, CD ₃ OD) δ = 8.18 (d, J = 9.2 Hz, 1H), 7.89 (d, J = 2.4 Hz, 1H), 7.82-7.74 (m, 2H), 7.54 (d, J = 8.0 Hz, 1H), 7.29 (t, J = 7.6 Hz, 1H), 5.55 (q, J = 7.2 Hz, 1H), 4.28-4.16 (m, 2H), 3.70-3.57 (m, 2H), 3.47 (t, J = 6.8 Hz, 2H), 2.77 (s, 3H), 2.65 (s, 3H), 2.32-2.17 (m, 4H), 2.17-2.06 (m, 4H), 1.71 (d, J = 7.2 Hz, 3H). LCMS [M+1] ⁺ : 484.2. 10-36

( R )-4-methyl- N -(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-7-(2,8-diazaspiro[4.5]deca -8-base) 呔

-1-amine hydrochloride ¹ H NMR (400 MHz, CD ₃ OD) δ = 8.15 (d, J = 9.6 Hz, 1H), 7.83 (d, J = 2.4 Hz, 1H), 7.78-7.71 (m, 2H), 7.54 (d, J = 7.6 Hz, 1H), 7.29 (t, J = 8.0 Hz, 1H), 5.55 (q, J = 6.8 Hz, 1H), 3.95-3.75 (m, 4H), 3.50 (t, J = 7.2 Hz, 2H), 3.28 (s, 2H), 2.76 (s, 3H), 2.65 (s, 3H), 2.15-2.08 (m, 2H), 1.96-1.83 (m, 4H), 1.70 (d, J = 6.8 Hz , 3H). LCMS [M+1] ⁺ : 484.2. 10-37

( R )-4-methyl- N -(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-7-(2-methyl-2,8-diazepine Spiro[4.5]dec-8-yl) 呔

-1-amine hydrochloride ¹ H NMR (400 MHz, CD ₃ OD) δ = 8.15 (d, J = 9.2 Hz, 1H), 7.81 (d, J = 2.0 Hz, 1H), 7.77-7.69 (m, 2H), 7.54 (d, J = 7.6 Hz, 1H), 7.29 (t, J = 8.0 Hz, 1H), 5.55 (q, J = 6.8 Hz, 1H), 3.94-3.70 (m, 6H), 3.31-3.24 (m, 1H), 3.08 (d, J = 11.6 Hz, 1H), 3.01 (s, 3H), 2.76 (s, 3H), 2.64 (s, 3H), 2.33-2.21 (m, 1H), 2.17-2.08 (m, 1H) , 2.01-1.87 (m, 4H), 1.69 (d, J = 6.8 Hz, 3H). LCMS [M+1] ⁺ : 498.3. 10-38

( R )-8-(1-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)

-6-yl)-2,8-diazaspiro[4.5]dec-1-one ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 7.81-7.74 (m, 2H), 7.63-7.58 (m, 3H), 7.50 (d, J = 7.6 Hz, 1H), 7.55-7.44 (m, 1H), 7.32-7.29 (m, 1H), 5.68-5.64 (m, 1H), 4.05-4.01 (m, 2H), 3.21-3.23 (m, 1H), 3.08-3.13 (m, 3H), 2.57 ( s, 3H), 2.53 (s, 3H), 2.06 (t, J = 6.8 Hz, 2H), 1.85-1.78 (m, 2H), 1.55 (d, J = 6.8 Hz, 3H), 1.50-1.52 (m , 2H). LCMS [M+1] ⁺ : 498.6. 10-39

( R )-2-(1-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)

-6-yl)-2,8-diazaspiro[4.5]dec-1-one hydrochloride ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 9.40 (br s, 1H), 9.17 (br s, 1H), 9.08-8.94 (m, 1H), 8.89 (dd, J = 1.2, 8.8 Hz, 1H), 8.70 (s, 1H), 8.39 (d, J = 9.2 Hz, 1H), 7.92 (d, J = 8.0 Hz, 1H), 7.54 (d, J = 7.6 Hz, 1H), 7.33 (t, J = 8.0 Hz, 1H), 5.50 (q, J = 6.4 Hz, 1H), 4.29-4.19 (m, 1H), 4.15-4.09 (m, 1H), 3.36-3.27 (m, 2H), 3.12-3.01 (m, 2H), 2.82 (s, 3H), 2.57 (s, 3H), 2.26 (br t, J = 6.8 Hz, 2H), 2.10-1.98 (m, 2H), 1.83 (br d, J = 12.8 Hz, 2H), 1.66 (d, J = 6.8 Hz, 3H). LCMS [M+1] ⁺ : 498.3. 10-40

( R )-2-methyl-8-(1-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)

-6-yl)-2,8-diazaspiro[4.5]dec-1-one ¹ H NMR (400 MHz, CD ₃ OD) δ = 8.12 (br d, J = 9.2 Hz, 1H), 7.81-7.64 (m, 3H), 7.52 (br d, J = 7.6 Hz, 1H), 7.27 ( br t, J = 7.6 Hz, 1H), 5.52 (q, J = 6.8 Hz, 1H), 4.31 (br d, J = 13.6 Hz, 2H), 3.55-3.39 (m, 4H), 2.88 (s, 3H ), 2.73 (s, 3H), 2.63 (s, 3H), 2.20 (br t, J = 6.8 Hz, 2H), 1.98 (br t, J = 12.8 Hz, 2H), 1.66 (br d, J = 7.2 Hz, 5H). LCMS [M+1] ⁺ : 512.2. 10-41

( R )-4-methyl- N -(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-7-(6-methyl-2,6-diazepine Spiro[3.4]oct-2-yl)

-1-amine hydrochloride ¹ H NMR (400 MHz, CD ₃ OD) δ = 8.14 (d, J = 9.2 Hz, 1H), 7.71 (d, J = 8.0 Hz, 1H), 7.55-7.49 (m, 1H), 7.55-7.47 ( m, 1H), 7.43-7.40 (m, 1H), 7.43-7.38 (m, 1H), 7.27 (t, J = 7.6 Hz, 1H), 7.18 (d, J = 2.0, 8.8 Hz, 1H), 5.52 (q, J = 7.2 Hz, 1H), 4.44-4.32 (m, 2H), 4.32-4.23 (m, 1H), 4.19-4.04 (m, 1H), 3.85-3.69 (m, 1H), 3.52-3.43 (m, 1H), 3.01 (s, 2H), 2.77-2.71 (m, 3H), 2.70-2.59 (m, 4H), 2.57-2.49 (m, 1H), 2.57-2.49 (m, 1H), 1.73 -1.63 (m, 3H). LCMS [M+1] ⁺ : 470.2. 10-42

( R )-7-(4-(dimethylamino)-4-methylpiperidin-1-yl)-4-methyl- N -(1-(2-methyl-3-(trifluoro (Methyl) phenyl) ethyl) 呔

-1-amine hydrochloride ¹ H NMR (400 MHz, CD ₃ OD) δ = 8.17 (d, J = 9.2 Hz, 1H), 7.87 (d, J = 2.8 Hz, 1H), 7.78-7.73 (m, 2H), 7.52 (d, J = 7.6 Hz, 1H), 7.27 (t, J = 8.0 Hz, 1H), 5.54 (q, J = 6.8 Hz, 1H), 4.50-4.42 (m, 2H), 3.42-3.34 (m, 2H), 2.88 (s, 6H), 2.75 (s, 3H), 2.63 (s, 3H), 2.24-2.15 (m, 2H), 2.12-2.01 (m, 2H), 1.69 (d, J = 6.8 Hz, 3H) , 1.57 (s, 3H). LCMS [M+1] ⁺ : 486.3. 10-43

( R )-4-methyl- N -(1-(naphthalene-1-yl)ethyl)-7-(piper

-1-base) 呔

-1-carbamate ¹ H NMR (400 MHz, CD ₃ OD) δ = 8.49 (s, 1H), 8.19 (d, J = 8.0 Hz, 1H), 8.10 (d, J = 9.2 Hz, 1H), 7.92-7.83 (m, 1H), 7.78-7.73 (m, 2H), 7.71-7.67 (m, 1H), 7.63 (d, J = 7.2 Hz, 1H), 7.53-7.44 (m, 2H), 7.43-7.37 (m, 1H) , 6.23-6.09 (m, 1H), 3.79-3.69 (m, 4H), 3.27-3.19 (m, 4H), 2.71 (s, 3H), 1.82 (d, J = 6.8 Hz, 3H). LCMS [M+1] ⁺ : 398.2. 10-44

(R)-7-(4-(azetidin-1-yl)piperidin-1-yl)-N-(1-(3-(difluoromethyl)-2-methylphenyl) Ethyl)-4-methyl

-1-amine hydrochloride ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 8.69-8.52 (m, 1H), 8.11 (br d, J = 9.2 Hz, 1H), 7.95 (br s, 1H), 7.76 (br d, J = 9.6 Hz, 1H), 7.67 (br s, 1H), 7.40 (br d, J = 7.6 Hz, 1H), 7.36-7.07 (m, 2H), 5.45 (br t, J = 6.8 Hz, 1H), 4.49 (br d, J = 13.2 Hz, 2H), 4.18-3.93 (m, 4H), 3.55-3.48 (m, 1H), 3.19-3.10 (m, 2H), 2.70 (s, 3H), 2.51-2.51 (m, 3H), 2.40-2.15 (m, 2H), 2.07-2.02 (m, 2H), 1.62 (d, J = 7.2 Hz, 3H), 1.56-1.41 (m, 2H). LCMS [M+1] ⁺ : 466.2. 10-45

(R) -N ⁷ , N ⁷ ,4-Trimethyl- N ¹ -(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)

-1,7-diamine ¹ H NMR (400 MHz, CD ₃ OD) δ = 8.12 (d, J = 8.8 Hz, 1H), 7.70 (d, J = 8.0 Hz, 1H), 7.57-7.44 (m, 3H), 7.27 (t, J = 8.0 Hz, 1H), 5.53 (q, J = 6.8 Hz, 1H), 3.34-3.32 (m, 6H), 2.80-2.71 (s, 3H), 2.63 (s, 3H), 1.67 (d, J = 7.2 Hz, 3H). LCMS [M+1] ⁺ : 389.2. 10-46

( R )-7-(3-(dimethylamino)azetidin-1-yl)-4-methyl- N -(1-(2-methyl-3-(trifluoromethyl )Phenyl) ethyl) 呔

-1-carbamate ¹ H NMR (400 MHz, CDCl ₃ ) δ = 8.56 (s, 1H), 7.92 (d, J = 8.8 Hz, 1H), 7.70 (d, J = 7.6 Hz, 1H), 7.49 (d, J = 7.6 Hz, 1H), 7.28-7.24 (m, 1H), 7.22 (d, J = 2.4 Hz, 1H), 7.11-7.03 (m, 1H), 5.68-5.55 (m, 1H), 4.25 (t, J = 8.0 Hz, 2H), 4.02-3.89 (m, 2H), 3.48-3.37 (m, 1H), 2.62 (s, 3H), 2.61 (s, 3H), 2.29 (s, 6H), 1.63 (d, J = 6.8 Hz, 3H). LCMS [M+1] ⁺ : 444.1. 10-47

( R )-3-methyl-1-(1-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)

-6-yl)azetidine-3-ol ¹ H NMR (400 MHz, CD ₃ OD) δ = 7.83 (d, J = 8.8 Hz, 1H), 7.69 (d, J = 7.6 Hz, 1H), 7.47 (d, J = 7.6 Hz, 1H), 7.22 (t, J = 7.6 Hz, 1H), 7.15 (d, J = 2.0 Hz, 1H), 7.02 (dd, J = 2.4, 8.8 Hz, 1H), 5.70 (q, J = 6.8 Hz, 1H), 4.03 (dd, J = 4.0, 8.0 Hz, 2H), 3.94 (d, J = 8.0 Hz, 2H), 2.61 (s, 3H), 2.57 (s, 3H), 1.63-1.59 (m, 6H). LCMS [M+1] ⁺ : 431.3. 10-48

( R )-1-(1-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)

-6-yl)azetidine-3-ol ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 14.61 (br s, 1H), 8.44 (br d, J = 6.4 Hz, 1H), 8.09 (d, J = 8.8 Hz, 1H), 7.77 (d , J = 8.0 Hz, 1H), 7.55 (d, J = 8.0 Hz, 1H), 7.46 (s, 1H), 7.34 (t, J = 7.6 Hz, 1H), 7.13 (dd, J = 2.0, 9.2 Hz , 1H), 5.96 (d, J = 6.0 Hz, 1H), 5.43 (br t, J = 6.8 Hz, 1H), 4.76-4.66 (m, 1H), 4.49-4.39 (m, 2H), 4.00-3.90 (m, 2H), 2.69 (s, 3H), 2.56 (s, 3H), 1.61 (d, J = 6.8 Hz, 3H). LCMS [M+1] ⁺ : 417.1. 10-49

( R )-7-(4-(3,3-Difluoropyrrolidin-1-yl)piperidin-1-yl)-4-methyl- N -(1-(2-methyl-3-( (Trifluoromethyl) phenyl) ethyl) 呔

-1-carbamate ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 8.16 (s, 1H), 7.80-7.74 (m, 2H), 7.62-7.54 (m, 2H), 7.51 (d, J = 7.6 Hz, 1H) , 7.42 (d, J = 6.4 Hz, 1H), 7.31 (t, J = 7.6 Hz, 1H), 5.71-5.62 (m, 1H), 4.02-3.98 (m, 2H), 3.04 -2.96 (m, 5H ), 2.80 (t, J = 7.2 Hz, 2H), 2.58 (s, 3H), 2.43-2.39 (m, 2H), 2.37-2.17 (m, 3H), 2.03-1.90 (m, 2H), 1.55 ( d, J = 7.2 Hz, 3H), 1.54-1.45 (m, 2H). LCMS [M+1] ⁺ : 534.4. 10-50

( R ) -N -(1-(3-Fluoro-5-(trifluoromethyl)phenyl)ethyl)-4-methyl-7-

Linyl

-1-amine ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 7.84 (d, J = 8.8 Hz, 1H), 7.64 (s, 1H), 7.55-7.62 (m, 3H), 7.48 (d, J = 10.4 Hz , 1H), 7.36 (d, J = 7.6 Hz, 1H), 5.50-5.54 (m, 1H), 3.84-3.82 (m, 4H), 3.42-3.44 (m, 4H), 2.55 (s, 3H), 1.61 (d, J = 7.2 Hz, 3H). LCMS [M+1] ⁺ : 435.2. 10-51

(R)-2-methyl-3-(1-((4-methyl-7-

Linyl

-1-yl)amino)ethyl)benzonitrile ¹ H NMR (400 MHz, CD ₃ OD) δ = 7.86 (d, J = 8.8 Hz, 1H), 7.77-7.68 (m, 1H), 7.58-7.52 (m, 2H), 7.46 (dd, J = 1.2 , 7.6 Hz, 1H), 7.22 (t, J = 8.0 Hz, 1H), 5.61 (q, J = 7.2 Hz, 1H), 3.92-3.84 (m, 4H), 3.49-3.41 (m, 4H), 2.72 (s, 3H), 2.59 (s, 3H), 1.61 (d, J = 6.8 Hz, 3H). LCMS [M+1] ⁺ : 388.3. 10-52

( R )-3-Fluoro-5-(1-((4-methyl-7-

Linyl

-1-yl)amino)ethyl)benzonitrile ¹ H NMR (400 MHz, CD ₃ OD) δ = 7.89 (d, J = 9.2 Hz, 1H), 7.63 (t, J = 1.2 Hz, 1H), 7.58-7.49 (m, 3H), 7.33-7.28 ( m, 1H), 5.42 (q, J = 6.8 Hz, 1H), 3.89-3.84 (m, 4H), 3.46-3.40 (m, 4H), 2.62 (s, 3H), 1.66 (d, J = 7.2 Hz , 3H). LCMS [M+1] ⁺ : 392.2. 10-53

3-((1 R )-1-((7-(6-oxa-3-azabicyclo[3.1.1]hept-3-yl)-4-methyl

-1-yl)amino)ethyl)-2-methylbenzonitrile formate ¹ H NMR (400 MHz, CDCl ₃ ) δ = 7.66 (t, J = 8.4 Hz, 2H), 7.48-7.36 (m, 2H), 7.28-7.25 (m, 2H), 7.15 (t, J = 7.6 Hz , 1H), 5.52-5.36 (m, 1H), 4.88 (d, J = 6.4 Hz, 2H), 3.92-3.73 (m, 4H), 3.49-3.35 (m, 1H), 2.72 (s, 3H), 2.57 (s, 3H), 2.01 (d, J = 9.2 Hz, 1H), 1.65 (d, J = 6.8 Hz, 3H). LCMS [M+1] ⁺ : 400.2. 10-54

3-(( R )-1-((7-((1 R ,4 R )-2-oxa-5-azabicyclo[2.2.1]hept-5-yl)-4-methyl

-1-yl)amino)ethyl)-2-methylbenzonitrile formate ¹ H NMR (400 MHz, CD ₃ OD) δ = 8.55 (br s, 1H), 8.04 (d, J = 8.8 Hz, 1H), 7.72 (d, J = 7.6 Hz, 1H), 7.52 (d, J = 7.6 Hz, 1H), 7.44-7.34 (m, 2H), 7.27 (t, J = 8.4 Hz, 1H), 5.47 (q, J = 6.8 Hz, 1H), 4.98 (s, 1H), 4.82 (s , 1H), 3.97 (d, J = 7.2 Hz, 1H), 3.88 (d, J = 7.6 Hz, 1H), 3.72 (d, J = 10.4 Hz, 1H), 3.43 (d, J = 10.4 Hz, 1H ), 2.73 (s, 3H), 2.69 (s, 3H), 2.11 (s, 2H), 1.64 (d, J = 7.2 Hz, 3H). LCMS [M+1] ⁺ : 400.2. 10-55

( R )-2-methyl-3-(1-((4-methyl-7-(piper

-1-base) 呔

-1-yl)amino)ethyl)benzonitrile formate ¹ H NMR (400 MHz, CD ₃ OD) δ = 8.49 (br s, 1H), 8.11 (d, J = 8.8 Hz, 1H), 7.79-7.69 (m, 3H), 7.52 (d, J = 7.2 Hz , 1H), 7.27 (t, J = 7.6 Hz, 1H), 5.50 (q, J = 6.8 Hz, 1H), 3.83-3.77 (m, 4H), 3.29-3.25 (m, 4H), 2.74 (s, 3H), 2.72 (s, 3H), 1.65 (d, J = 6.8 Hz, 3H). LCMS [M+1] ⁺ : 387.1. 10-56

3-(( R )-1-((7-(( S )-hexahydropyridine

And [2,1- c ][1,4]

-8(1 H )-yl)-4-methyl

-1-yl)amino)ethyl)-2-methylbenzonitrile formate ¹ H NMR (400 MHz, CD ₃ OD) δ = 8.53 (s, 1H), 7.98 (d, J = 8.8 Hz, 1H), 7.72 (d, J = 8.0 Hz, 1H), 7.67-7.59 (m, 2H), 7.50 (d, J = 7.6 Hz, 1H), 7.25 (t, J = 7.6 Hz, 1H), 5.59-5.49 (m, 1H), 4.14 (d, J = 11.6 Hz, 1H), 3.98 ( d, J = 12.0 Hz, 1H), 3.93-3.83 (m, 2H), 3.78-3.68 (m, 1H), 3.37 (d, J = 10.8 Hz 1H), 3.16 (dt, J = 2.8, 12.0 Hz, 1H), 2.99 (br d, J = 11.6 Hz, 1H), 2.81 (d, J = 11.2 Hz 1H), 2.73 (s, 3H), 2.71-2.67 (m, 1H), 2.66 (s, 3H), 2.53-2.37 (m, 3H), 1.63 (d, J = 6.8 Hz, 3H). LCMS [M+1] ⁺ : 443.2. 10-57

( R )-3-(1-((7-(4-(dimethylamino)piperidin-1-yl)-4-methyl

-1-yl)amino)ethyl)-2-methylbenzonitrile formate ¹ H NMR (400 MHz, CD ₃ OD) δ = 8.53 (br s, 1H), 8.03 (br d, J = 9.2 Hz, 1H), 7.76-7.62 (m, 3H), 7.52 (br d, J = 8.4 Hz, 1H), 7.27 (t, J = 7.6 Hz, 1H), 5.55-5.45 (m, 1H), 4.39 (br d, J = 12.8 Hz, 2H), 3.13 (t, J = 12.8 Hz, 2H ), 3.03-2.94 (m, 1H), 2.73 (s, 3H), 2.68 (s, 3H), 2.62-2.54 (m, 6H), 2.16 (d, J = 11.6 H, 2H), 1.76-1.67 ( m, 2H), 1.65 (d, J = 7.2 Hz, 3H). LCMS [M+1] ⁺ : 429.2. 10-58

( R )-3-(1-((7-(3-hydroxy-3-methylazetidin-1-yl)-4-methyl

-1-yl)amino)ethyl)-2-methylbenzonitrile ¹ H NMR (400 MHz, CD ₃ OD) δ = 8.10 (d, J = 8.8 Hz, 1H), 7.73 (d, J = 7.6 Hz, 1H), 7.55-7.51 (m, 1H), 7.34-7.26 ( m, 2H), 7.16 (dd, J = 2.0, 9.2 Hz, 1H), 5.42 (d, J = 6.8 Hz, 1H), 4.20-4.16 (m, 2H), 4.14-4.08 (m, 2H), 2.74 (s, 3H), 2.73 (s, 3H), 1.66 (d, J = 7.2 Hz, 3H), 1.62 (s, 3H). LCMS [M+1] ⁺ : 388.2. 10-59

( R )- N -(1-(2-chloro-4-fluorophenyl)ethyl)-4-methyl-7-

Linyl

-1-amine hydrochloride ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 14.8 (s, 1H), 8.60 (d, J = 6.4 Hz, 1H), 8.17 (d, J = 9.2 Hz, 1H), 7.92 (d, J = 0.8 Hz, 1H), 7.77 (dd, J = 2.4, 9.6 Hz, 1H), 7.58 (dd, J = 6.4, 8.8 Hz, 1H), 7.44 (dd, J = 2.8, 8.8 Hz, 1H), 7.22 -7.15 (m, 1H), 5.47 (m, 1H), 3.79-3.86 (m, 4H), 3.74-3.66 (m, 4H), 2.73 (s, 3H), 1.63 (d, J = 6.8 Hz, 3H ). LCMS [M+1] ⁺ : 401.1. 10-60

N -(1-(2-Chloro-3-methylphenyl)ethyl)-4-methyl-7-

Linyl

-1-amine ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 8.18 (s, 1H), 8.09-8.07 (m, 1H), 7.80-7.79 (m, 1H), 7.74-7.71 (m, 1H), 7.32- 7.31 (m, 1H), 7.23-7.21 (m, 1H), 7.18-7.14 (m, 1H), 5.61-5.54 (m, 1H), 3.85-3.82 (m, 4H), 3.63-3.62 (m, 4H) ), 2.66 (s, 3H), 2.37 (s, 3H), 1.62-1.61 (m, 3H). LCMS [M+1] ⁺ : 397.1. 10-61

( R )-4-methyl- N -(1-(3-methyl-5-(trifluoromethyl)phenyl)ethyl)-7-

Linyl

-1-amine ¹ H NMR (400 MHz, CD ₃ OD) δ = 8.19-8.16 (m, 1H), 7.74-7.73 (m, 2H) 7.53 (s, 2H), 7.34 (s, 1H), 5.29-5.27 (m, 1H), 3.91-3.89 (m, 4H), 3.71-3.69 (m, 4H), 2.77 (s, 3H), 2.39 (s, 3H), 1.71-1.69 (m, 3H). LCMS [M+1] ⁺ : 431.1. 10-62

7-(( S )-6-fluoro-1,4-diazepan-1-yl)-4-methyl- N -(( R )-1-(2-methyl-3-( (Trifluoromethyl) phenyl) ethyl) 呔

-1-amine hydrochloride ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 14.77 (s, 1H), 9.84 (s, 1H), 8.92 (s, 1H), 8.78-8.77 (m, 1H), 8.19-8.16 (m, 1H), 7.89 (s, 1H), 7.83-7.82 (m, 1H), 7.73-7.71 (m, 1H), 7.59-7.55 (m, 1H), 7.37-7.33 (m, 1H), 5.49-5.37 ( m, 2H), 4.61-4.55 (m, 1H), 4.25-4.21 (m, 1H), 4.09-3.97 (m, 2H), 3.62-3.58 (m, 2H), 3.48 (s, 2H), 2.73 ( s, 3H), 2.56 (s, 3H), 1.86-1.84 (m, 3H). LCMS [M+1] ⁺ : 462.1. 10-63

7-(( R )-6-fluoro-1,4-diazepan-1-yl)-4-methyl- N -(( R )-1-(2-methyl-3-( (Trifluoromethyl) phenyl) ethyl) 呔

-1-amine hydrochloride ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 14.75 (s, 1H), 9.76 (s, 1H), 8.92 (s, 1H), 8.69 (s, 1H), 8.19-8.16 (m, 1H) , 7.85 (s, 1H), 7.79-7.77 (m, 1H), 7.73-7.71 (m, 1H), 7.57-7.55 (m, 1H), 7.37-7.33 (m, 1H), 5.51-5.34 (m, 2H), 4.56-4.50 (m, 1H), 4.20 (s, 1H), 4.10-4.00 (m, 2H), 3.55 (s, 2H), 3.49 (s, 2H), 2.73 (s, 3H), 2.58 (s, 3H), 1.85-1.84 (m, 3H). LCMS [M+1] ⁺ : 462.1. 10-64

( R )-5-(1-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)

-6-yl)-1,2,5-thiadiazepine 1,1-dioxide ¹ H NMR (400 MHz, methanol- d ₄ ) δ = 8.02 (d, J = 9.1 Hz, 1H), 7.69 (d, J = 7.8 Hz, 1H), 7.55-7.48 (m, 3H), 7.24 (t , J = 7.9 Hz, 1H), 5.64 (q, J = 6.9 Hz, 1H), 4.17-4.09 (m, 4H), 3.58-3.54 (m, 2H), 3.39 (t, J = 6.0 Hz, 2H) , 2.66 (s, 3H), 2.61 (d, J = 1.6 Hz, 3H), 1.64 (d, J = 7.0 Hz, 3H). LCMS [M+1] ⁺ : 494.4 10-65

( R ) -N -(1-(3-(Difluoromethyl)-2-methylphenyl)ethyl)-4-methyl-7-

Linyl

-1-amine hydrochloride ¹ H NMR (400 MHz, CD ₃ OD) δ 8.16 (d, J = 9.3 Hz, 1H), 7.78-7.69 (m, 2H), 7.59 (d, J = 7.8 Hz, 1H), 7.38 (d, J = 7.6 Hz, 1H), 7.23 (t, J = 7.7 Hz, 1H), 6.94 (t, J = 55.3 Hz, 1H), 5.53 (q, J = 6.9 Hz, 1H), 4.61 (s, 3H), 3.93-3.87 (m, 4H), 3.73-3.64 (m, 4H), 2.75 (s, 3H), 2.56 (s, 3H), 1.66 (d, J = 6.9 Hz, 3H). LCMS [M+1] ⁺ : 413.2. 10-66

( R )-7-(3-(dimethylamino)-3-methylazetidin-1-yl)-4-methyl- N -(1-(2-methyl-3- (Trifluoromethyl)phenyl)ethyl)

-1-amine ¹ H NMR (400 MHz, CDCl ₃ ) δ = 7.76 (d, J = 8.8 Hz, 1H), 7.67 (d, J = 7.8 Hz, 1H), 7.53 (d, J = 7.8 Hz, 1H), 7.25- 7.19 (m, 1H), 6.90 (dd, J = 8.9, 2.2 Hz, 1H), 6.39 (d, J = 2.2 Hz, 1H), 5.85 (s, 1H), 4.88 (s, 1H), 3.87 (dd , J = 7.1, 3.5 Hz, 2H), 3.76 (dd, J = 7.1, 3.6 Hz, 2H), 2.68 (s, 3H), 2.56 (d, J = 1.7 Hz, 3H), 2.23 (s, 6H) , 1.65 (d, J = 6.7 Hz, 3H), 1.39 (s, 3H). LCMS [M+1] ⁺ : 458.4. 10-67

( R )-3-(1-((7-(4,4-difluoropiperidin-1-yl)-4-methyl

-1-yl)amino)ethyl)-2-methylbenzonitrile ¹ H NMR (400 MHz, CD ₃ OD) δ 7.96 (d, J = 9.1 Hz, 1H), 7.76-7.63 (m, 3H), 7.50 (dd, J = 7.7, 1.4 Hz, 1H), 7.25 (t , J = 7.8 Hz, 1H), 5.58 (q, J = 7.0 Hz, 1H), 3.75 (t, J = 5.8 Hz, 5H), 2.74 (s, 3H), 2.64 (s, 3H), 2.21-2.10 (m, 5H), 1.64 (d, J = 7.0 Hz, 3H). LCMS [M+1] ⁺ : 422.2. 10-68

( R )-3-(1-((7-(4-(azetidin-1-yl)piperidin-1-yl)-4-methyl

-1-yl)amino)ethyl)-2-methylbenzonitrile ¹ H NMR (400 MHz, CD ₃ OD) δ = 7.87-7.83 (m, 1H), 7.73 (dd, J = 8.0, 1.4 Hz, 1H), 7.57-7.53 (m, 2H), 7.48 (dd, J = 7.6, 1.3 Hz, 1H), 7.24 (t, J = 7.8 Hz, 1H), 5.62 (q, J = 6.9 Hz, 1H), 4.12 (d, J = 13.0 Hz, 2H), 2.98 (td, J = 12.7, 2.6 Hz, 2H), 2.74 (s, 3H), 2.59 (s, 3H), 2.45-2.34 (m, 1H), 2.12 (p, J = 7.1 Hz, 2H), 1.94-1.85 (m, 2H), 1.62 (d, J = 6.9 Hz, 3H), 1.37 (t, J = 12.1 Hz, 2H). LCMS [M+1] ⁺ : 441.2. 10-69

( R )-2-Methyl-3-(1-((4-methyl-7-(6-methyl-5-oxo-2,6-diazaspiro[3.4]oct-2- Base) eh

-1-yl)amino)ethyl)benzonitrile ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.80 (d, J = 8.9 Hz, 1H), 7.74 (dd, J = 7.9, 1.4 Hz, 1H), 7.59 (dd, J = 7.6, 1.4 Hz, 1H), 7.30 (dd, J = 9.2, 6.6 Hz, 2H), 7.19 (d, J = 2.3 Hz, 1H), 7.01 (dd, J = 8.9, 2.2 Hz, 1H), 5.58-5.49 (m, 1H ), 4.11 (t, J = 8.2 Hz, 2H), 4.00 (dd, J = 7.7, 4.3 Hz, 2H), 2.79 (s, 3H), 2.66 (s, 3H), 2.44 (t, J = 6.9 Hz , 2H), 1.53 (d, J = 7.0 Hz, 3H). LCMS [M+1] ⁺ : 441.4. 10-70

( R )-2-methyl-3-(1-((4-methyl-7-(4-(1-methyl-1 H -pyrazol-4-yl)piper

-1-base) 呔

-1-yl)amino)ethyl)benzonitrile ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 7.81 (d, J = 8.9 Hz, 1H), 7.75 (dd, J = 8.0, 1.4 Hz, 1H), 7.65-7.57 (m, 3H), 7.41 (d, J = 6.8 Hz, 1H), 7.36 (s, 1H), 7.30 (t, J = 7.8 Hz, 1H), 7.25 (s, 1H), 5.56 (q, J = 6.7 Hz, 1H), 3.75 (s, 3H), 3.59-3.53 (m, 4H), 3.05 (t, J = 5.1 Hz, 4H), 2.67 (s, 3H), 2.53 (s, 3H), 1.55 (d, J = 6.9 Hz, 3H). LCMS [M+1] ⁺ : 467.2. 10-71

2-Methyl-3-(( R )-1-((4-methyl-7-((1 R ,4 R )-5-methyl-2,5-diazabicyclo[2.2.2] Oct-2-yl)

-1-yl)amino)ethyl)benzonitrile ¹ H NMR (400 MHz, CDCl ₃ ) δ = 7.77 (d, J = 9.2 Hz, 1H), 7.67 (d, J = 7.2 Hz, 1H), 7.45 (dd, J = 1.2, 7.6 Hz, 1H), 7.26 (s, 1H), 7.22-7.14 (m, 2H), 6.56 (d, J = 2.4 Hz, 1H), 5.73 (br t, J = 6.4 Hz, 1H), 4.95 (br d, J = 4.8 Hz , 1H), 4.03 (br s, 1H), 3.90 (m, 1H), 3.31 (m, 1H), 3.10 (m, 1H), 2.96-2.87 (m, 2H), 2.68 (d, J = 7.2 Hz , 6H), 2.47 (s, 3H), 2.24-2.13 (m, 1H), 2.07-1.96 (m, 1H), 1.93 (m, 1H), 1.61 (d, J = 6.4 Hz, 3H). LCMS [M+1] ⁺ : 427.2 10-72

( R )-4-methyl- N -(1-(2-methylpyridin-3-yl)ethyl)-7-

Linyl

-1-amine ¹ H NMR (400 MHz, CD ₃ OD) δ = 8.21 (dd, J = 1.6, 4.8 Hz, 1H), 7.90 (br d, J = 8.4 Hz, 1H), 7.85 (dd, J = 1.6, 7.6 Hz , 1H), 7.62-7.53 (m, 2H), 7.16 (dd, J = 1.6, 7.6 Hz, 1H), 5.59 (q, J = 6.8 Hz, 1H), 3.96-3.84 (m, 4H), 3.50- 3.40 (m, 4H), 2.73 (s, 3H), 2.61 (s, 3H), 1.64 (d, J = 6.8 Hz, 3H). LCMS [M+1] ⁺ : 364.2. 10-73

( R )-2-methyl-3-(1-((4-methyl-7-(6-methyl-2,6-diazaspiro[3.4]oct-2-yl)

-1-yl)amino)ethyl)benzonitrile formate ¹ H NMR (400 MHz, CD ₃ OD) δ = 8.55 (s, 1H), 8.01 (d, J = 9.2 Hz, 1H), 7.72 (d, J = 8.0 Hz, 1H), 7.55-7.50 (m, 1H), 7.30-7.26 (m, 1H), 7.25 (d, J = 2.0 Hz, 1H), 7.12-7.08 (m, 1H), 5.57-5.41 (m, 1H), 4.24-4.16 (m, 2H) , 4.16-4.10 (m, 2H), 3.04 (s, 2H), 2.84 (t, J = 6.8 Hz, 2H), 2.74 (s, 3H), 2.68 (s, 3H), 2.52 (s, 3H), 2.32 (t, J = 6.8 Hz, 2H), 1.64 (d, J = 6.8 Hz, 3H). LCMS [M+1] ⁺ : 427.3. 10-74

( R )-3-(1-((7-(3-(dimethylamino)-3-methylazetidin-1-yl)-4-methyl

-1-yl)amino)ethyl)-2-methylbenzonitrile hydrochloride ¹ H NMR (400 MHz, CD ₃ OD) δ = 8.19 (d, J = 9.2 Hz, 1H), 7.79 (d, J = 7.2 Hz, 1H), 7.61-7.49 (m, 2H), 7.34-7.19 ( m, 2H), 5.44 (q, J = 7.2 Hz, 1H), 4.56 (dd, J = 5.6, 9.6 Hz, 2H), 4.29 (dd, J = 6.0, 10.0 Hz, 2H), 2.94 (s, 6H ), 2.76 (d, J = 9.6 Hz, 6H), 1.83 (s, 3H), 1.69 (d, J = 7.2 Hz, 3H). LCMS [M+1] ⁺ : 415.3. 10-75

( R )-3-(1-((7-(3-(dimethylamino)azetidin-1-yl)-4-methyl

-1-yl)amino)ethyl)-2-methylbenzonitrile hydrochloride ¹ H NMR (400 MHz, CD ₃ OD) δ = 8.19 (d, J = 9.2 Hz, 1H), 7.79 (d, J = 8.0 Hz, 1H), 7.60-7.51 (m, 2H), 7.33-7.24 ( m, 2H), 5.44 (q, J = 6.8 Hz, 1H), 4.67-4.57 (m, 2H), 4.51 (td, J = 5.2, 10.4 Hz, 2H), 4.47-4.38 (m, 1H), 3.01 (s, 6H), 2.76 (d, J = 7.2 Hz, 6H), 1.69 (d, J = 7.2 Hz, 3H). LCMS [M+1] ⁺ : 401.2. 10-76

( R )-7-(3-(dimethylamino)azetidin-1-yl) -N -(1-(2-fluoro-3-(trifluoromethyl)phenyl)ethyl )-4-methyl

-1-amine ¹ H NMR (400 MHz, DMSO- d ₆ ): δ = 7.79 (d, J = 8.8 Hz, 1H), 7.71 (t, J = 6.8 Hz, 1H), 7.60 (t, J = 6.8 Hz, 1H) , 7.33-7.22 (m, 2H), 7.20 (s, 1H), 7.08-6.93 (m, 1H), 5.73-5.70 (m, 1H), 4.21-4.04 (m, 2H), 3.90-3.70 (m, 2H), 3.29-3.27 (m, 1H), 2.52-2.51 (m, 3H), 2.16 (s, 6H), 1.61 (d, J = 6.8 Hz, 3H). LCMS [M+1] ⁺ : 448.3. 10-77

( R ) -N -(1-(2-Fluoro-3-(trifluoromethyl)phenyl)ethyl)-4-methyl-7-

Linyl

-1-amine ¹ H NMR (400 MHz, CD ₃ OD) δ 7.91 (dd, J = 13.0, 8.8 Hz, 1H), 7.71-7.55 (m, 3H), 7.48 (d, J = 7.5 Hz, 1H), 7.18 (t , J = 7.9 Hz, 1H), 5.72 (q, J = 7.0 Hz, 1H), 3.97-3.88 (m, 4H), 3.53-3.45 (m, 4H), 2.62-2.57 (m, 3H), 1.69 ( d, J = 7.0 Hz, 3H). LCMS [M+1] ⁺ : 435.2. 10-78

( R )-7-(3-(dimethylamino)-3-methylazetidin-1-yl) -N -(1-(2-fluoro-3-(trifluoromethyl) (Phenyl) ethyl)-4-methyl

-1-amine ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.79 (d, J = 8.9 Hz, 1H), 7.71 (t, J = 7.3 Hz, 1H), 7.60 (t, J = 7.3 Hz, 1H), 7.32 -7.19 (m, 3H), 7.03 (dd, J = 8.8, 2.2 Hz, 1H), 3.83-3.74 (m, 4H), 3.29 (s, 3H), 2.15 (s, 6H), 1.61 (d, J = 7.1 Hz, 3H), 1.34 (s, 3H). LCMS [M+1] ⁺ : 462.1. 10-79

( R )-2-methyl-3-(1-((4-methyl-7-(5-methyl-8-oxa-2,5-diazaspiro[3.5]non-2-yl ) Eh

-1-yl)amino)ethyl)benzonitrile formate ¹ H NMR (400 MHz, CD ₃ OD) δ = 7.99 (d, J = 9.0 Hz, 1H), 7.73 (dd, J = 7.9, 1.3 Hz, 1H), 7.50 (dt, J = 7.7, 1.3 Hz, 1H), 7.29-7.23 (m, 2H), 7.16-7.12 (m, 1H), 5.51 (q, J = 7.0 Hz, 1H), 4.32 (d, J = 9.4 Hz, 2H), 3.86-3.75 (m , 6H), 2.73 (s, 3H), 2.66 (s, 3H), 2.63-2.60 (m, 2H), 2.50 (s, 3H), 1.63 (d, J = 6.9 Hz, 3H). LCMS [M+1] ⁺ : 443.2. 10-80

( R )-2-methyl-3-(1-((4-methyl-7-(6-oxa-2-azaspiro[3.4]oct-2-yl)

-1-yl)amino)ethyl)benzonitrile hydrochloride ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 14.65 (s, 1H), 8.47 (s, 1H), 8.11 (d, J = 9.0 Hz, 1H), 7.77 (d, J = 8.0 Hz, 1H) , 7.64 (d, J = 7.5 Hz, 1H), 7.48 (s, 1H), 7.34 (t, J = 7.8 Hz, 1H), 7.18-7.11 (m, 1H), 5.37-5.29 (m, 1H), 4.25-4.15 (m, 4H), 3.91-3.86 (m, 2H), 3.78 (t, J = 6.9 Hz, 2H), 2.69 (s, 3H), 2.66 (s, 3H), 2.24 (t, J = 6.9 Hz, 2H), 1.60 (d, J = 7.0 Hz, 3H). LCMS [M+1] ⁺ : 414.2. 10-81

3-(( R )-1-((7-(( R )-hexahydropyrrolo[1,2- a ]pyridine

-2(1 H )-yl)-4-methyl

-1-yl)amino)ethyl)-2-methylbenzonitrile ¹ H NMR (400 MHz, CD ₃ OD) δ 7.87 (d, J = 9.8 Hz, 1H), 7.73 (dd, J = 7.9, 1.4 Hz, 1H), 7.63-7.56 (m, 2H), 7.47 (d , J = 7.6 Hz, 1H), 7.23 (t, J = 7.8 Hz, 1H), 5.61 (q, J = 6.9 Hz, 1H), 4.20 (d, J = 11.9 Hz, 1H), 4.05 (d, J = 12.5 Hz, 1H), 3.26-3.02 (m, 3H), 2.73 (s, 3H), 2.59 (s, 3H), 2.45 (td, J = 11.4, 3.4 Hz, 1H), 2.28 (q, J = 9.1 Hz, 2H), 2.06-1.83 (m, 4H), 1.62 (d, J = 6.9 Hz, 3H), 1.60-1.51 (m, 1H). LCMS [M+1] ⁺ : 427.3. 10-82

2-Methyl-3-(( R )-1-((4-methyl-7-(( R )-octahydro-2 H -pyrido[1,2- a ]pyridine

-2-base)

-1-yl)amino)ethyl)benzonitrile hydrochloride ¹ H NMR (400 MHz, methanol- d ₄ ) δ 8.25 (d, J = 9.3 Hz, 1H), 7.97 (d, J = 2.4 Hz, 1H), 7.89-7.77 (m, 2H), 7.56 (d, J = 7.6 Hz, 1H), 7.30 (t, J = 7.8 Hz, 1H), 5.47 (q, J = 7.0 Hz, 1H), 4.60 (t, J = 11.8 Hz, 2H), 3.67 (d, J = 12.5 Hz, 1H), 3.59 (t, J = 11.6 Hz, 2H), 3.49-3.35 (m, 1H), 3.33-3.26 (m, 1H), 3.18-3.07 (m, 1H), 2.80 (s, 3H) ), 2.76 (s, 3H), 2.21-2.13 (m, 1H), 2.05-2.00 (m, 3H), 2.00-1.92 (m, 1H), 1.84-1.68 (m, 5H). LCMS [M+1] ⁺ : 441.3. 10-83

( R )-2-methyl-3-(1-((4-methyl-7-(3-methyl-3-

Alkylazetidine-1-yl)

-1-yl)amino)ethyl)benzonitrile formate ¹ H NMR (400 MHz, CD ₃ OD) δ = 8.55 (s, 1H), 8.02 (d, J = 9.0 Hz, 1H), 7.74 (dd, J = 7.9, 1.4 Hz, 1H), 7.52 (dd, J = 7.7, 1.4 Hz, 1H), 7.32-7.22 (m, 2H), 7.13 (dd, J = 9.0, 2.3 Hz, 1H), 5.50 (q, J = 6.9 Hz, 1H), 4.01 (t, J = 7.4 Hz, 2H), 3.88 (dd, J = 8.3, 5.9 Hz, 2H), 3.75 (t, J = 4.5 Hz, 3H), 2.72 (s, 3H), 2.69 (s, 3H), 2.59-2.54 (m, 4H), 1.64 (d, J = 7.0 Hz, 3H), 1.48 (s, 3H). LCMS [M+1] ⁺ : 457.3. 10-84

( R )-2-methyl-3-(1-((4-methyl-7-(5-methyl-2,5-diazaspiro[3.4]oct-2-yl)

-1-yl)amino)ethyl)benzonitrile ¹ H NMR (400 MHz, CD ₃ OD) δ 7.88 (d, J = 8.9 Hz, 1H), 7.76 (dd, J = 7.9, 1.4 Hz, 1H), 7.51 (dd, J = 7.7, 1.4 Hz, 1H ), 7.26 (t, J = 7.8 Hz, 1H), 7.18 (d, J = 2.3 Hz, 1H), 7.09 (dd, J = 8.9, 2.3 Hz, 1H), 5.63 (q, J = 6.9 Hz, 1H ), 4.27 (dd, J = 8.5, 2.6 Hz, 2H), 3.92 (d, J = 8.5 Hz, 2H), 2.84 (t, J = 7.3 Hz, 2H), 2.76 (s, 3H), 2.61 (s , 3H), 2.54 (s, 3H), 2.28-2.20 (m, 2H), 1.96-1.84 (m, 2H), 1.64 (d, J = 6.9 Hz, 3H). LCMS [M+1] ⁺ : 427.3. 10-85

7-((1 R ,4 R )-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-N-(( R )-1-(3-(difluoromethyl) )-2-Fluorophenyl)ethyl)-4-methyl

-1-amine ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.78 (d, J = 9.0 Hz, 1H), 7.57 (t, J = 7.4 Hz, 1H), 7.45 (t, J = 7.1 Hz, 1H), 7.33 -7.15 (m, 4H), 5.73-5.65 (m, 1H), 4.92 (s, 1H), 4.75 (s, 1H), 3.91-3.84 (m, 1H), 3.75-3.69 (m, 1H), 3.67 -3.60 (m, 1H), 3.27-3.21 (m, 1H), 2.04-1.93 (m, 2H), 1.60 (d, J = 7.1 Hz, 3H), 1.24 (s, 1H). LCMS [M+1] ⁺ : 429.3. 10-86

N -(( R )-1-(3-(Difluoromethyl)-2-fluorophenyl)ethyl)-7-(( S )-hexahydropyridine

And [2,1- c ][1,4]

-8(1 H )-yl)-4-methyl

-1-carbamate ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.15 (s, 1H), 7.82 (d, J = 9.7 Hz, 1H), 7.64-7.54 (m, 2H), 7.46 (t, J = 7.1 Hz, 1H), 7.38-7.34 (m, 1H), 7.27-7.18 (m, 2H), 5.70 (t, J = 7.0 Hz, 1H), 4.12-4.04 (m, 1H), 3.92-3.77 (m, 3H) , 3.64-3.53 (m, 1H), 3.27-3.20 (m, 1H), 3.03-2.90 (m, 2H), 2.78-2.71 (m, 1H), 2.70-2.67 (m, 1H), 2.54 (s, 3H), 2.42-2.34 (m, 1H), 2.32-2.22 (m, 2H), 1.62 (d, J = 7.1 Hz, 3H). LCMS [M+1] ⁺ : 472.4. 10-87

3-(( R )-1-((7-((1 R ,4 R )-2-oxa-5-azabicyclo[2.2.1]hept-5-yl)-4-methyl

-1-yl)amino)ethyl)-2-(trifluoromethyl)benzonitrile hydrochloride ¹ H NMR (400 MHz, CD ₃ OD) δ = 8.42 (d, J = 9.2 Hz, 1H), 8.37 (d, J = 8.0 Hz, 1H), 8.13 (d, J = 7.6 Hz, 1H), 7.98 (t, J = 7.9 Hz, 1H), 7.82-7.77 (m, 1H), 7.75-7.71 (m, 1H), 5.90 (q, J = 7.0 Hz, 1H), 5.37 (s, 1H), 5.14 ( s, 1H), 4.30 (d, J = 7.6 Hz, 1H), 4.19 (d, J = 7.7 Hz, 1H), 4.08-4.01 (m, 1H), 3.80 (d, J = 10.5 Hz, 1H), 3.02 (s, 2H), 2.43 (d, J = 3.0 Hz, 3H), 2.03 (d, J = 6.9 Hz, 3H). LCMS [M+1] ⁺ : 454.2. Example 11-1 (R )-(4-(1-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)

-6-yl)piperidine

-1-yl)(oxetan-3-yl)methanone

-1-基)呔

-1-胺（20.0 mg，46.6 µmol，1.00當量）及氧雜環丁烷-3-羧酸（5.70 mg，55.9 µmol，1.20當量）於DMF（0.50 mL）中之溶液中添加HATU（21.3mg，55.9 µmol，1.20當量）及N,N- 二異丙基乙胺（18.1 mg，140 µmol，24.3 µL，3.00當量）。將混合物在25℃下攪拌1小時，隨後藉由製備型HPLC（Waters Xbridge 150×25 mm×5 um；移動相：移動相A：[水（10 mM NH₄ HCO₃ ），移動相B：乙腈]；B%：27%-57%）純化，得到呈灰白色固體狀之(R )-(4-(1-甲基-4-((1-(2-甲基-3-(三氟甲基)苯基)乙基)胺基)呔

-6-基)哌

-1-基)(氧雜環丁烷-3-基)甲酮（9.00 mg，17.4 µmol，37.4%產率，99.4%純度）。LCMS [M+1]⁺ : 514.3。To ( R )-4-methyl- N -(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-7-(piper

-1-base) 呔

A solution of -1-amine (20.0 mg, 46.6 µmol, 1.00 equivalent) and oxetane-3-carboxylic acid (5.70 mg, 55.9 µmol, 1.20 equivalent) in DMF (0.50 mL) was added with HATU (21.3 mg , 55.9 µmol, 1.20 equivalents) and N,N -diisopropylethylamine (18.1 mg, 140 µmol, 24.3 µL, 3.00 equivalents). The mixture was stirred at 25°C for 1 hour, followed by preparative HPLC (Waters Xbridge 150×25 mm×5 um; mobile phase: mobile phase A: [water (10 mM NH ₄ HCO ₃ ), mobile phase B: acetonitrile ]; B%: 27%-57%) to obtain ( R )-(4-(1-methyl-4-((1-(2-methyl-3-(trifluoromethyl)) as an off-white solid (Phenyl) Ethyl) Amino) Ethyl

-6-yl)piperidine

-1-yl)(oxetan-3-yl)methanone (9.00 mg, 17.4 µmol, 37.4% yield, 99.4% purity). LCMS [M+1] ⁺ : 514.3.

¹ H NMR (400 MHz, CD ₃ OD) δ = 8.02 (d, J = 9.2 Hz, 1H), 7.73-7.63 (m, 3H), 7.50 (d, J = 7.6 Hz, 1H), 7.25 (t, J = 8.0 Hz, 1H), 5.63 (q, J = 7.2 Hz, 1H), 4.89 (br s, 4H), 4.33-4.22 (m, 1H), 3.89-3.78 (m, 2H), 3.69-3.58 ( m, 4H), 3.55-3.47 (m, 2H), 2.67 (s, 3H), 2.61 (s, 3H), 1.64 (d, J = 6.8 Hz, 3H).

(R )-(4-(1-甲基-4-((1-(2-甲基-3-(三氟甲基)苯基)乙基)胺基)呔

-6-基)哌

-1-基)(四氫-2H -哌喃-4-基)甲酮 ¹ H NMR (400 MHz, CD₃ OD) δ = 7.95 - 7.88 (m, 1H), 7.70 (d, J = 8.0 Hz, 1H), 7.63 - 7.57 (m, 2H), 7.48 (d, J = 7.6 Hz, 1H), 7.23 (t, J = 7.6 Hz, 1H), 5.72 (d, J = 6.8 Hz, 1H), 4.02 - 3.94 (m, 2H), 3.88 - 3.78 (m, 4H), 3.61 - 3.49 (m, 6H), 3.10 - 3.00 (m, 1H), 2.65 - 2.57 (m, 6H), 1.89 - 1.77 (m, 2H), 1.71 - 1.64 (m, 2H), 1.63 (d, J = 6.8 Hz, 3H)。LCMS [M+1]⁺ : 542.4。 11-3

(R )-(4-(1-甲基-4-((1-(2-甲基-3-(三氟甲基)苯基)乙基)胺基)呔

-6-基)哌

-1-基)(1-(三氟甲基)環丙基)甲酮 ¹ H NMR (400 MHz, CD₃ OD) δ = 7.94 - 7.89 (m, 1H), 7.70 (d,J = 7.6 Hz, 1H), 7.65 - 7.59 (m, 2H), 7.48 (d,J = 7.6 Hz, 1H), 7.23 (t,J = 7.6 Hz, 1H), 5.72 (q,J = 6.8 Hz, 1H), 3.91 (br s, 4H), 3.60 - 3.52 (m, 4H), 2.65 - 2.58 (m, 6H), 1.63 (d,J = 6.8 Hz, 3H), 1.45 - 1.39 (m, 2H), 1.34 - 1.25 (m, 2H)。 LCMS [M+1]⁺ : 566.4。 11-4

(4-(1-甲基-4-(((R )-1-(2-甲基-3-(三氟甲基)苯基)乙基)胺基)呔

-6-基)哌

-1-基)((R )-四氫呋喃-3-基)甲酮 ¹ H NMR (400 MHz, CD₃ OD) δ 7.90 (d,J = 8.8 Hz, 1H), 7.70 (d,J = 7.8 Hz, 1H), 7.62 - 7.57 (m, 2H), 7.49 - 7.45 (m, 1H), 7.22 (t,J = 7.8 Hz, 1H), 5.71 (q,J = 6.9 Hz, 1H), 4.03 - 3.85 (m, 3H), 3.85 - 3.78 (m, 5H), 3.52 (tt,J = 11.6, 3.8 Hz, 6H), 2.24 - 2.09 (m, 2H), 1.62 (d,J = 6.9 Hz, 3H)。LCMS [M+1]⁺ : 528.3。 11-5

(4-(1-甲基-4-(((R )-1-(2-甲基-3-(三氟甲基)苯基)乙基)胺基)呔

-6-基)哌

-1-基)((S )-四氫呋喃-3-基)甲酮 ¹ H NMR (400 MHz, CD₃ OD) δ 8.11 (d,J = 9.2 Hz, 1H), 7.75 - 7.68 (m, 4H), 7.52 (d,J = 7.8 Hz, 1H), 7.27 (t,J = 7.9 Hz, 1H), 5.61 (q,J = 6.9 Hz, 1H), 4.05 - 3.69 (m, 12H), 3.55 (tt,J = 8.3, 6.3 Hz, 1H), 2.72 (s, 3H), 2.63 (d,J = 1.8 Hz, 3H), 2.26 - 2.13 (m, 2H), 1.67 (d,J = 7.0 Hz, 3H)。LCMS [M+1]⁺ : 528.3。 11-6

(R )-3-(1-((7-(4-(環丙烷羰基)哌

-1-基)-4-甲基吡啶并[3,4-d ]嗒

-1-基)胺基)乙基)-2-甲基苯甲腈 ¹ H NMR (400 MHz, CD₃ OD) δ = 9.04 (s, 1H), 7.71 (d,J = 7.9 Hz, 1H), 7.50 (d,J = 7.6 Hz, 1H), 7.36 (s, 1H), 7.26 (t,J = 7.7 Hz, 1H), 5.59 (q,J = 6.8 Hz, 1H), 4.66 - 4.55 (m, 4H), 4.03 - 3.94 (m, 4H), 3.86 - 3.80 (m, 4H), 2.73 (s, 3H), 2.63 (s, 3H), 2.08 - 2.00 (m, 1H), 1.62 (d,J = 6.9 Hz, 3H), 0.97 - 0.85 (m, 4H)。LCMS [M+1]⁺ : 456.4。 實例12-1 (R )-4-甲基-7-(4-(1-甲基-1H -吡唑-4-基)哌

-1-基)-N -(1-(2-甲基-3-(三氟甲基)苯基)乙基)吡啶并[3,4-d]嗒

-1-胺

Following the teaching of General Reaction Scheme III and the method of preparing Example 11-1, the following compounds of formula (I) as shown in Table 11, Examples 11-2 to 11-6, were prepared. Table 11 Example # structure Spectral data 11-2

( R )-(4-(1-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)

-6-yl)piperidine

-1-yl)(tetrahydro- 2H -piperan-4-yl)methanone ¹ H NMR (400 MHz, CD ₃ OD) δ = 7.95-7.88 (m, 1H), 7.70 (d, J = 8.0 Hz, 1H), 7.63-7.57 (m, 2H), 7.48 (d, J = 7.6 Hz, 1H), 7.23 (t, J = 7.6 Hz, 1H), 5.72 (d, J = 6.8 Hz, 1H), 4.02-3.94 (m, 2H), 3.88-3.78 (m, 4H), 3.61-3.49 (m, 6H), 3.10-3.00 (m, 1H), 2.65-2.57 (m, 6H), 1.89-1.77 (m, 2H), 1.71-1.64 (m, 2H), 1.63 (d, J = 6.8 Hz , 3H). LCMS [M+1] ⁺ : 542.4. 11-3

( R )-(4-(1-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)

-6-yl)piperidine

-1-yl)(1-(trifluoromethyl)cyclopropyl)methanone ¹ H NMR (400 MHz, CD ₃ OD) δ = 7.94-7.89 (m, 1H), 7.70 (d, J = 7.6 Hz, 1H), 7.65-7.59 (m, 2H), 7.48 (d, J = 7.6 Hz, 1H), 7.23 (t, J = 7.6 Hz, 1H), 5.72 (q, J = 6.8 Hz, 1H), 3.91 (br s, 4H), 3.60-3.52 (m, 4H), 2.65-2.58 ( m, 6H), 1.63 (d, J = 6.8 Hz, 3H), 1.45-1.39 (m, 2H), 1.34-1.25 (m, 2H). LCMS [M+1] ⁺ : 566.4. 11-4

(4-(1-methyl-4-((( R )-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)

-6-yl)piperidine

-1-yl)(( R )-tetrahydrofuran-3-yl)methanone ¹ H NMR (400 MHz, CD ₃ OD) δ 7.90 (d, J = 8.8 Hz, 1H), 7.70 (d, J = 7.8 Hz, 1H), 7.62-7.57 (m, 2H), 7.49-7.45 (m , 1H), 7.22 (t, J = 7.8 Hz, 1H), 5.71 (q, J = 6.9 Hz, 1H), 4.03-3.85 (m, 3H), 3.85-3.78 (m, 5H), 3.52 (tt, J = 11.6, 3.8 Hz, 6H), 2.24-2.09 (m, 2H), 1.62 (d, J = 6.9 Hz, 3H). LCMS [M+1] ⁺ : 528.3. 11-5

(4-(1-methyl-4-((( R )-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)

-6-yl)piperidine

-1-yl)(( S )-tetrahydrofuran-3-yl)methanone ¹ H NMR (400 MHz, CD ₃ OD) δ 8.11 (d, J = 9.2 Hz, 1H), 7.75-7.68 (m, 4H), 7.52 (d, J = 7.8 Hz, 1H), 7.27 (t, J = 7.9 Hz, 1H), 5.61 (q, J = 6.9 Hz, 1H), 4.05-3.69 (m, 12H), 3.55 (tt, J = 8.3, 6.3 Hz, 1H), 2.72 (s, 3H), 2.63 (d, J = 1.8 Hz, 3H), 2.26-2.13 (m, 2H), 1.67 (d, J = 7.0 Hz, 3H). LCMS [M+1] ⁺ : 528.3. 11-6

( R )-3-(1-((7-(4-(cyclopropanecarbonyl)piper

-1-yl)-4-methylpyrido[3,4- d ]

-1-yl)amino)ethyl)-2-methylbenzonitrile ¹ H NMR (400 MHz, CD ₃ OD) δ = 9.04 (s, 1H), 7.71 (d, J = 7.9 Hz, 1H), 7.50 (d, J = 7.6 Hz, 1H), 7.36 (s, 1H) , 7.26 (t, J = 7.7 Hz, 1H), 5.59 (q, J = 6.8 Hz, 1H), 4.66-4.55 (m, 4H), 4.03-3.94 (m, 4H), 3.86-3.80 (m, 4H ), 2.73 (s, 3H), 2.63 (s, 3H), 2.08-2.00 (m, 1H), 1.62 (d, J = 6.9 Hz, 3H), 0.97-0.85 (m, 4H). LCMS [M+1] ⁺ : 456.4. Example 12-1 ( R )-4-methyl-7-(4-(1-methyl- 1H -pyrazol-4-yl)piper

-1-yl) -N -(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)pyrido[3,4-d]ta

-1-amine

-1(2H )-酮（5.00 g，25.6 mmol，1.00當量）於POCl₃ （137 g，893 mmol，83.0 mL，34.9當量）中之溶液中逐滴添加N,N- 二異丙基乙胺（9.91 g，76.7 mmol，13.4 mL，3當量），隨後將反應在110℃下攪拌2小時。在此時間後，將混合物冷卻至25℃且在真空下濃縮，得到殘餘物，將殘餘物在0℃下用乙酸乙酯（300 mL）稀釋，用緩慢添加的碳酸氫鈉飽和水溶液將其調節至pH=7。將合併之有機相用鹽水（200 mL×2）洗滌，經無水硫酸鈉乾燥，過濾，且在真空下濃縮，得到呈粉紅色固體狀之1,7-二氯-4-甲基吡啶并[3,4-d ]嗒

（4.10 g，19.2 mmol，74.9%產率）。Step A: At 25°C, to 7-chloro-4-methylpyrido[3,4- d ]

-1(2 H )-ketone (5.00 g, 25.6 mmol, 1.00 equivalent) in POCl ₃ (137 g, 893 mmol, 83.0 mL, 34.9 equivalent) was added dropwise N,N -diisopropyl ethyl Amine (9.91 g, 76.7 mmol, 13.4 mL, 3 equivalents), then the reaction was stirred at 110°C for 2 hours. After this time, the mixture was cooled to 25°C and concentrated under vacuum to give a residue, which was diluted with ethyl acetate (300 mL) at 0°C and adjusted with slowly added saturated aqueous sodium bicarbonate To pH=7. The combined organic phase was washed with brine (200 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain 1,7-dichloro-4-methylpyrido[ 3,4- d ]

(4.10 g, 19.2 mmol, 74.9% yield).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.65 (s, 1H), 8.22 (s, 1H), 3.02 (s, 3H).

（300 mg，1.40 mmol，1.00當量）及(R )-1-(2-甲基-3-(三氟甲基)苯基)乙-1-胺（285 mg，1.40 mmol，1.00當量）於DMSO（5.00 mL）中之溶液中添加氟化鉀（244 mg，4.20 mmol，98.5 µL，3.00當量）及N,N- 二異丙基乙胺（543 mg，4.20 mmol，732 µL，3.00當量）。將混合物在130℃下攪拌12小時，隨後冷卻至室溫且添加水（20.0 mL）。將混合物用乙酸乙酯（10.0 mL×3）萃取，且將合併之有機層用鹽水（5.00 mL×2）洗滌，經硫酸鈉乾燥，過濾，且在減壓下濃縮，得到殘餘物。將殘餘物藉由管柱層析法（SiO₂ ，石油醚/乙酸乙酯＝1/0至5/1）純化，得到呈黃色固體狀之(R )-7-氯-4-甲基-N -(1-(2-甲基-3-(三氟甲基)苯基)乙基)吡啶并[3,4-d]嗒

-1-胺（320 mg，840 µmol，60.0%產率）。LCMS [M+1]⁺ : 381.0。Step B: To 1,7-dichloro-4-methylpyrido[3,4- d ]

(300 mg, 1.40 mmol, 1.00 equivalent) and ( R )-1-(2-methyl-3-(trifluoromethyl)phenyl)ethan-1-amine (285 mg, 1.40 mmol, 1.00 equivalent) in Add potassium fluoride (244 mg, 4.20 mmol, 98.5 µL, 3.00 equivalents) and N,N -diisopropylethylamine (543 mg, 4.20 mmol, 732 µL, 3.00 equivalents) to the solution in DMSO (5.00 mL) . The mixture was stirred at 130°C for 12 hours, then cooled to room temperature and water (20.0 mL) was added. The mixture was extracted with ethyl acetate (10.0 mL×3), and the combined organic layer was washed with brine (5.00 mL×2), dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 1/0 to 5/1) to obtain ( R )-7-chloro-4-methyl- as a yellow solid N -(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)pyrido[3,4-d]

-1-amine (320 mg, 840 µmol, 60.0% yield). LCMS [M+1] ⁺ : 381.0.

-1-胺（40.0 mg，105 µmol，1.00當量）、1-(1-甲基-1H -吡唑-4-基)哌

（58.9 mg，210 µmol，2.00當量，TFA鹽）、碳酸銫（171 mg，525 µmol，5.00當量）及RuPhos Pd G3（8.79 mg，10.5 µmol，0.10當量）於二

烷（1.00 mL）中之混合物脫氣且用氮氣沖洗3次，隨後將混合物在氮氣氛圍下在80℃下攪拌10小時。將反應混合物藉由在20℃下加水（15.0 mL）來淬滅，且隨後用乙酸乙酯（5.00 mL×3）萃取。將合併之有機層用鹽水（5.00 mL）洗滌，經硫酸鈉乾燥，過濾，且在減壓下濃縮，得到殘餘物。將殘餘物藉由製備型HPLC（管柱：Phenomenex Gemini-NX C18 75×30 mm×3 um；移動相：A相：水（0.04% HCl），B相：乙腈；梯度：B%：30%-60%）純化，得到呈淺黃色固體狀之(R )-4-甲基-7-(4-(1-甲基-1H -吡唑-4-基)哌

-1-基)-N -(1-(2-甲基-3-(三氟甲基)苯基)乙基)吡啶并[3,4-d ]嗒

-1-胺（9.51 mg，15.1%產率，HCl鹽）。LCMS [M+1]⁺ : 511.1。Step C: Add ( R )-7-chloro-4-methyl- N -(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)pyrido[3,4-d ]despair

-1-amine (40.0 mg, 105 µmol, 1.00 equivalent), 1-(1-methyl-1 H -pyrazol-4-yl)piper

(58.9 mg, 210 µmol, 2.00 equivalent, TFA salt), cesium carbonate (171 mg, 525 µmol, 5.00 equivalent) and RuPhos Pd G3 (8.79 mg, 10.5 µmol, 0.10 equivalent) in two

The mixture in alkane (1.00 mL) was degassed and flushed with nitrogen 3 times, then the mixture was stirred at 80°C for 10 hours under a nitrogen atmosphere. The reaction mixture was quenched by adding water (15.0 mL) at 20°C, and then extracted with ethyl acetate (5.00 mL×3). The combined organic layer was washed with brine (5.00 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was subjected to preparative HPLC (column: Phenomenex Gemini-NX C18 75×30 mm×3 um; mobile phase: phase A: water (0.04% HCl), phase B: acetonitrile; gradient: B%: 30% -60%) to obtain ( R )-4-methyl-7-(4-(1-methyl-1 H -pyrazol-4-yl)piperidine as a pale yellow solid

-1-yl) -N -(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)pyrido[3,4- d ]

-1-amine (9.51 mg, 15.1% yield, HCl salt). LCMS [M+1] ⁺ : 511.1.

-1-胺

¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 9.00 (s, 1H), 7.72 (d, J = 7.6 Hz, 1H), 7.57 (d, J = 6.4 Hz, 1H), 7.52 (d, J = 7.6 Hz, 1H), 7.48 (s, 1H), 7.36 (s, 1H), 7.35-7.29 (m, 1H), 7.25 (s, 1H), 5.63 (quin, J = 6.8 Hz, 1H), 3.88 -3.83 (m, 4H), 3.75 (s, 2H), 3.78-3.72 (m, 1H), 3.04-2.98 (m, 4H), 2.56 (s, 6H), 1.55 (d, J = 6.8 Hz, 3H ). Example 12-2 7-(6-oxa-3-azabicyclo[3.1.1]hept-3-yl)-4-methyl- N -(( R )-1-(2-methyl-3 -(Trifluoromethyl)phenyl)ethyl)pyrido[3,4- d ]

-1-amine

-1-胺（50.0 mg，131 µmol，1.00當量）及6-氧雜-3-氮雜雙環[3.1.1]庚烷（35.6 mg，263 µmol，2.00當量，HCl）於二

烷（2.00 mL）中之溶液中添加碳酸銫（171 mg，525 µmol，4.00當量）、RuPhos（6.10 mg，13.1 µmol，0.10當量）及Pd₂ (dba)₃ （6.00 mg，6.60 µmol，0.05當量）。將混合物在110℃下攪拌2小時，隨後冷卻至25℃，過濾，且將濾液用水（10.0 mL）淬滅，且隨後用乙酸乙酯（30.0 mL）萃取。將合併之有機層用鹽水（10.0 mL）洗滌，經無水硫酸鈉乾燥，過濾，且在減壓下濃縮，得到殘餘物。將殘餘物藉由製備型HPLC（管柱：Waters Xbridge BEH C18 100×25 mm×5 um；移動相：A相：水（10 mM NH₄ HCO₃ ），B相：乙腈；梯度：B%：30%-60%）純化，得到呈黃色固體狀之7-(6-氧雜-3-氮雜雙環[3.1.1]庚-3-基)-4-甲基-N-((R)-1-(2-甲基-3-(三氟甲基)苯基)乙基)吡啶并[3,4-d]嗒

-1-胺（8.64 mg，18.9 µmol，14.4%產率）。LCMS [M+1]⁺ : 444.1。To (R)-7-chloro-4-methyl-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)pyrido[3,4-d]

-1-amine (50.0 mg, 131 µmol, 1.00 equivalent) and 6-oxa-3-azabicyclo[3.1.1]heptane (35.6 mg, 263 µmol, 2.00 equivalent, HCl) in two

Add cesium carbonate (171 mg, 525 µmol, 4.00 equivalents), RuPhos (6.10 mg, 13.1 µmol, 0.10 equivalents) and Pd ₂ (dba) ₃ (6.00 mg, 6.60 µmol, 0.05 equivalents) to the solution in alkane (2.00 mL) ). The mixture was stirred at 110°C for 2 hours, then cooled to 25°C, filtered, and the filtrate was quenched with water (10.0 mL), and then extracted with ethyl acetate (30.0 mL). The combined organic layer was washed with brine (10.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was subjected to preparative HPLC (column: Waters Xbridge BEH C18 100×25 mm×5 um; mobile phase: phase A: water (10 mM NH ₄ HCO ₃ ), phase B: acetonitrile; gradient: B%: 30%-60%) to obtain 7-(6-oxa-3-azabicyclo[3.1.1]hept-3-yl)-4-methyl-N-((R) as a yellow solid -1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)pyrido[3,4-d]

-1-amine (8.64 mg, 18.9 µmol, 14.4% yield). LCMS [M+1] ⁺ : 444.1.

¹ H NMR (400 MHz, DMSO- d6 ) δ = 9.03 (s, 1H), 7.74 (d, J = 7.6 Hz, 1H), 7.57 (s, 1H), 7.52 (d, J = 8.0 Hz, 1H) , 7.31 (t, J = 8.0 Hz, 1H), 7.27 (s, 1H), 5.66 (t, J = 7.2 Hz, 1H), 4.80 (d, J = 6.4 Hz, 2H), 3.91-3.90 (m, 2H), 3.75-3.68 (m, 2H), 3.23-3.16 (m, 1H), 2.57 (s, 6H), 1.95 (d, J = 9.2 Hz, 1H), 1.55 (d, J = 7.2 Hz, 3H ).

SFC conditions: Chiralcel OD-3 3 µm, 0.46 cm inner diameter × 5 cm L; mobile phase: A is SFC CO2, and B is MeOH (0.05% isopropylamine); gradient: B in A increases from 10% within 3 minutes To 40%; flow rate: 4.0 ml/min; column temperature: 35°C; wavelength: 220 nm; system back pressure: 100 bar.

(R )-4-甲基-N -(1-(2-甲基-3-(三氟甲基)苯基)乙基)-7-(2-氧雜-6-氮雜螺[3.3]庚-6-基)吡啶并[3,4-d ]嗒

-1-胺 ¹ H NMR (400 MHz, DMSO-d₆ ) δ = 8.94 (s, 1H), 7.72 (d,J = 7.6 Hz, 1H), 7.52 (d,J = 7.6 Hz, 2H), 7.34 - 7.28 (m, 1H), 7.10 (s, 1H), 5.67 - 5.57 (m, 1H), 4.78 (s, 4H), 4.29 (s, 4H), 2.56 - 2.52 (m, 6H), 1.54 (d,J = 6.8 Hz, 3H)。LCMS [M+1]⁺ : 444.1。 12-4

7-((2R ,6S )-2,6-二甲基

啉基)-4-甲基-N -((R )-1-(2-甲基-3-(三氟甲基)苯基)乙基)吡啶并[3,4-d]嗒

-1-胺鹽酸鹽 ¹ H NMR (400 MHz, DMSO-d₆ ) δ = 14.73 (s, 1H), 9.23 (s, 1H), 9.19 (br s, 1H), 8.04 (s, 1H), 7.89 (d,J = 7.6 Hz, 1H), 7.55 (d,J = 7.6 Hz, 1H), 7.37 - 7.35 (m, 1H), 5.45 - 5.41 (m, 1H), 4.76 - 4.73 (m, 2H), 3.67 - 3.63 (m, 2H), 2.78 - 2.74 (m, 5H), 2.56 (s, 3H), 1.64 (d,J = 6.8 Hz, 3H), 1.23 (d,J = 4.8 Hz, 6H)。LCMS [M+1]⁺ : 460.1。 12-5

7-((2R ,6R )-2,6-二甲基

啉基)-4-甲基-N -((R )-1-(2-甲基-3-(三氟甲基)苯基)乙基)吡啶并[3,4-d ]嗒

-1-胺鹽酸鹽 ¹ H NMR (400 MHz, DMSO-d₆ ) δ = 14.66 (s, 1H), 9.23 (s, 1H), 9.00 (s, 1H), 7.90 (s, 1H), 7.83 (d,J = 7.6 Hz, 1H), 7.56 (d,J = 7.6 Hz, 1H), 7.36 (t,J = 8.0 Hz, 1H), 5.48 - 5.37 (m, 1H), 4.17-4.08 (m, 2H), 4.06 - 4.02 (m, 2H), 3.74 - 3.69 (m, 2H), 2.73 (s, 3H), 2.56 (s, 3H), 1.63 (d,J = 6.8 Hz, 3H), 1.19 (d,J = 6.4 Hz, 6H)。LCMS [M+1]⁺ : 460.1。 12-6

7-((2S ,6S )-2,6-二甲基

啉基)-4-甲基-N -((R )-1-(2-甲基-3-(三氟甲基)苯基)乙基)吡啶并[3,4-d ]嗒

-1-胺鹽酸鹽 ¹ H NMR (400 MHz, DMSO-d₆ ) δ = 14.65 (s, 1H), 9.25 (s, 1H), 8.92 (s, 1H), 7.91 - 7.78 (m, 2H), 7.57 (d,J = 8.0 Hz, 1H), 7.41 - 7.32 (m, 1H), 5.49 - 5.37 (m, 1H), 4.18 - 4.09 (m, 2H), 4.09 - 4.00 (m, 2H), 3.76 - 3.63 (m, 2H), 2.73 (s, 3H), 2.56 (s, 3H), 1.63 (d,J = 7.2 Hz, 3H), 1.20 (d,J = 6.4 Hz, 6H)。LCMS [M+1]⁺ : 460.1。 12-7

(R )-4-甲基-1-(4-甲基-1-((1-(2-甲基-3-(三氟甲基)苯基)乙基)胺基)吡啶并[3,4-d ]嗒

-7-基)哌啶-4-醇 ¹ H NMR (400 MHz, CD₃ OD) δ = 9.19 (s, 1H), 7.68 (d,J = 8.0 Hz, 1H), 7.58 - 7.51 (m, 2H), 7.32 - 7.26 (m, 1H), 5.49 (q,J = 6.8 Hz, 1H), 4.46 (br s, 2H), 3.58 - 3.51 (m, 2H), 2.75 (s, 3H), 2.61 (s, 3H), 1.81 - 1.68 (m, 4H), 1.66 (d,J = 6.8 Hz, 3H), 1.31 (s, 3H)。LCMS [M+1]⁺ : 460.1。 12-8

7-((1S ,4S )-2-氧雜-5-氮雜雙環[2.2.1]庚-5-基)-4-甲基-N -((R )-1-(2-甲基-3-(三氟甲基)苯基)乙基)吡啶并[3,4-d ]嗒

-1-胺 ¹ H NMR (400 MHz, CD₃ OD) δ = 8.96 (s, 1H), 7.68 (d,J = 8.0 Hz, 1H), 7.49 (d,J = 7.6 Hz, 1H), 7.29 - 7.19 (m, 1H), 7.10 (s, 1H), 5.74 - 5.61 (m, 1H), 5.15 (s, 1H), 4.80 (s, 1H), 3.95 (dd,J = 1.2, 7.6 Hz, 1H), 3.85 (d,J = 7.2 Hz, 1H), 3.66 (dd,J = 1.2, 10.4 Hz, 1H), 3.51 (d,J = 10.4 Hz, 1H), 2.61 (s, 6H), 2.14 - 1.99 (m, 2H), 1.61 (d,J = 6.8 Hz, 3H)。LCMS [M+1]⁺ : 444.2。 12-9

7-((1R ,4R )-2-氧雜-5-氮雜雙環[2.2.1]庚-5-基)-4-甲基-N -((R )-1-(2-甲基-3-(三氟甲基)苯基)乙基)吡啶并[3,4-d ]嗒

-1-胺 ¹ H NMR (400 MHz, DMSO-d₆ ) δ = 8.96 (s, 1H), 7.67 (d,J = 8.0 Hz, 1H), 7.48 (d,J = 7.6 Hz, 1H), 7.25 - 7.22 (m, 1H), 7.09 (s, 1H), 5.68 - 5.66 (m, 1H), 5.15 (s, 1H), 4.79 (s, 1H), 3.96 - 3.93 (m, 1H), 3.86 - 3.84 (m, 1H), 3.68 - 3.65 (m, 1H), 3.51 -3.49 (m, 1H), 2.61 - 2.60 (m, 6H), 2.06 (s, 2H), 1.61 (d,J = 7.2 Hz, 3H)。LCMS [M+1]⁺ : 444.1。 12-10

(R )-2-甲基-3-(1-((4-甲基-7-

啉基吡啶并[3,4-d ]嗒

-1-基)胺基)乙基)苯甲腈 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.00 (s, 1H), 7.71 (d,J = 8.0 Hz, 1H), 7.61 (d,J = 1.2 7.6, Hz, 1H), 7.53 (d,J = 6.8 Hz, 1H), 7.40 (s, 1H), 7.32 (t,J = 7.6 Hz, 1H), 5.53 (m, 1H), 3.74 - 3.83 (m, 4H), 3.63 - 3.73 (m, 4H), 2.66 (s, 3H), 2.56 (s, 3H), 1.54 (d,J = 6.8 Hz, 3H)。LCMS [M+1]⁺ : 389.1 12-11

4-甲基-N -((R )-1-(2-甲基-3-(三氟甲基)苯基)乙基)-7-(((S )-1-甲基吡咯啶-3-基)氧基)吡啶并[3,4-d ]嗒

-1-胺鹽酸鹽 ¹ H NMR (400 MHz, DMSO-d₆ ) δ = 9.44 (s, 1H), 8.25 (s, 1H), 7.75 (d,J = 7.6 Hz, 1H), 7.56 (d,J = 7.6 Hz, 1H), 7.37 - 7.33 (m, 1H), 5.81 - 5.77 (m, 1H), 5.48 - 5.43 (m, 1H), 4.12 - 3.73 (m, 3H), 3.41 - 3.23 (m, 2H), 2.93 - 2.83 (m, 6H), 2.66 - 2.57 (m, 1H), 2.55 (s, 3H), 2.33 - 2.22 (m, 1H), 1.58 (d,J = 6.8 Hz, 3H)。LCMS [M+1]⁺ : 446.1。 12-12

(R )-4-甲基-N -(1-(2-甲基-3-(三氟甲基)苯基)乙基)-7-((1-甲基氮雜環丁烷-3-基)氧基)吡啶并[3,4-d]嗒

-1-胺 ¹ H NMR (400 MHz, DMSO-d₆ ) δ = 9.07 (s, 1H), 7.84 (s, 1H), 7.73 - 7.71 (m, 1H), 7.51 (d,J = 7.6 Hz, 1H), 7.32 - 7.30 (m, 1H), 5.64 - 5.59 (m, 1H), 5.27 - 5.24 (m, 1H), 3.79 - 3.75 (m, 2H), 3.06 - 3.01 (m, 2H), 2.61 (s, 3H), 2.56 (s, 3H), 2.31 (s, 3H), 1.52 (d,J = 6.8 Hz, 3H)。LCMS [M+1]⁺ : 432.1。 12-13

(R )-4-(4-甲基-1-((1-(2-甲基-3-(三氟甲基)苯基)乙基)胺基)吡啶并[3,4-d ]嗒

-7-基)硫

啉1,1-二氧化物 ¹ H NMR (400 MHz, CD₃ OD) δ = 9.31 (s, 1H), 7.81 (s, 1H), 7.71 (d,J = 8.0 Hz, 1H), 7.54 (d,J = 8.0 Hz, 1H), 7.29 (t,J = 8.0 Hz, 1H), 5.53 (q,J = 6.8 Hz, 1H), 4.50 (br s, 4H), 3.30 (br s, 4H), 2.81 (s, 3H), 2.62 (s, 3H), 1.68 (d,J = 6.8 Hz, 3H)。LCMS [M+1]⁺ : 480.2。 12-14

7-((S )-六氫吡

并[2,1-c ][1,4]

-8(1H )-基)-4-甲基-N -((R )-1-(2-甲基-3-(三氟甲基)苯基)乙基)吡啶并[3,4-d ]嗒

-1-胺 ¹ H NMR (400 MHz, CD₃ OD) δ = 9.32 (s, 1H), 7.90 (br s, 1H), 7.78 (d,J = 7.6 Hz, 1H), 7.55 (d,J = 8.0 Hz, 1H), 7.30 (t,J = 7.6 Hz, 1H), 5.55 (q,J = 6.8 Hz, 1H), 5.25 - 5.01 (m, 2H), 4.29 - 4.09 (m, 2H), 4.08 - 3.98 (m, 1H), 3.93 - 3.34 (m, 8H), 2.83 (s, 3H), 2.64 (s, 3H), 1.72 (d,J = 6.8 Hz, 3H)。LCMS [M+1]⁺ : 487.2。 12-15

(R )-7-(4-(二甲基胺基)哌啶-1-基)-4-甲基-N -(1-(2-甲基-3-(三氟甲基)苯基)乙基)吡啶并[3,4-d ]嗒

-1-胺 ¹ H NMR (400 MHz, CD₃ OD) δ = 8.94 (s, 1H), 7.68 (d,J = 8.0 Hz, 1H), 7.48 (d,J = 7.8 Hz, 1H), 7.32 (s, 1H), 7.23 (t,J = 7.6 Hz, 1H), 5.67 (q,J = 6.8 Hz, 1H), 4.77 - 4.65 (m, 2H), 3.05 - 2.94 (m, 2H), 2.61 - 2.58 (m, 6H), 2.57 - 2.48 (m, 1H), 2.03 - 1.97 (m, 2H), 1.60 (d,J = 6.8 Hz, 3H), 1.55 - 1.43 (m, 2H)。LCMS [M+1]⁺ : 473.3。 12-16

(R )-6-甲基-2-(4-甲基-1-((1-(2-甲基-3-(三氟甲基)苯基)乙基)胺基)吡啶并[3,4-d ]嗒

-7-基)-2,6-二氮雜螺[3.4]辛-5-酮 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.15 (s, 1H), 7.68 (d,J = 8.0 Hz, 1H), 7.54 (d,J = 7.6 Hz, 1H), 7.32 (t,J = 8.0 Hz, 1H), 7.28 (s, 1H), 5.35 (q,J = 6.8 Hz, 1H), 4.30 (d,J = 8.4 Hz, 2H), 4.19 (d,J = 2.8, 9.2 Hz, 2H), 3.34 (t,J = 6.8 Hz, 2H), 2.78 (s, 3H), 2.69 (s, 3H), 2.52 (s, 3H), 2.41 (t,J = 6.8 Hz, 2H), 1.55 (d,J = 6.8 Hz, 3H)。LCMS [M+1]⁺ : 485.1。 12-17

(R )-4-甲基-N -(1-(2-甲基-3-(三氟甲基)苯基)乙基)-7-(6-甲基-2,6-二氮雜螺[3.4]辛-2-基)吡啶并[3,4-d ]嗒

-1-胺鹽酸鹽 ¹ H NMR (400 MHz, CD₃ OD) δ = 9.25 (br s, 1H), 7.83 - 7.70 (m, 1H), 7.55 (br d,J = 7.6 Hz, 1H), 7.46 - 7.18 (m, 2H), 5.57 - 5.48 (m, 1H), 4.84 - 4.68 (m, 1H), 4.55 - 4.27 (m, 3H), 4.07 - 4.01 (m, 1H), 3.99 - 3.67 (m, 2H), 3.58 - 3.43 (m, 1H), 3.03 (s, 3H), 2.79 (s, 3H), 2.71 - 2.48 (m, 5H), 1.69 (d,J = 7.2 Hz, 3H)。LCMS [M+1]⁺ : 471.2。 12-18

(R )-7-(4-(二甲基胺基)-4-甲基哌啶-1-基)-4-甲基-N -(1-(2-甲基-3-(三氟甲基)苯基)乙基)吡啶并[3,4-d ]嗒

-1-胺 ¹ H NMR (400 MHz, CD₃ OD) δ = 9.26 (s, 1H), 7.77 (t,J = 4.0 Hz, 2H), 7.55 (d,J = 7.6 Hz, 1H), 7.31 (t,J = 8.0 Hz, 1H), 5.53 (q,J = 6.8 Hz, 1H), 4.99 - 4.92 (m, 2H), 3.46 - 3.36 (m, 2H), 2.89 (s, 6H), 2.80 (s, 3H), 2.64 (s, 3H), 2.22 (br d,J = 12.4 Hz, 2H), 2.07 - 1.96 (m, 2H), 1.71 (d,J = 6.8 Hz, 3H), 1.61 (s, 3H)。LCMS [M+1]⁺ : 487.2。 12-19

(R )-7-(3-(二甲基胺基)-3-甲基氮雜環丁烷-1-基)-4-甲基-N -(1-(2-甲基-3-(三氟甲基)苯基)乙基)吡啶并[3,4-d ]嗒

-1-胺 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.93 (s, 1H), 7.72 (d,J = 7.6 Hz, 1H), 7.52 (d,J = 7.2 Hz, 1H), 7.45 (d,J = 6.8 Hz, 1H), 7.31 (t,J = 8.0 Hz, 1H), 7.09 (s, 1H), 5.68 - 5.57 (m, 1H), 3.94 - 3.86 (m, 2H), 3.80 (dd,J = 3.2, 8.0 Hz, 2H), 2.55 (br s, 3H), 2.54 (s, 3H), 2.15 (s, 6H), 1.53 (d,J = 7.2 Hz, 3H), 1.32 (s, 3H)。LCMS [M+1]⁺ : 459.4。 12-20

(R )-7-(3-(二甲基胺基)氮雜環丁烷-1-基)-4-甲基-N -(1-(2-甲基-3-(三氟甲基)苯基)乙基)吡啶并[3,4-d ]嗒

-1-胺 鹽酸鹽 ¹ H NMR (400 MHz, CD₃ OD) δ = 9.27 (s, 1H), 7.71 (d,J =7.2 Hz, 1H), 7.54 (d,J = 7.6 Hz, 1H), 7.44 (s, 1H), 7.32 - 7.27 (m, 1H), 5.52 (q,J =7.2 Hz, 1H), 4.72 - 4.65 (m, 2H), 4.55 (m, 2H), 4.42 (br s, 1H), 3.01 (s, 6H), 2.80 (s, 3H), 2.62 (s, 3H), 1.68 (d,J =7.2 Hz, 3H)。LCMS [M+1]⁺ : 445.2。 12-21

(R )-3-甲基-1-(4-甲基-1-((1-(2-甲基-3-(三氟甲基)苯基)乙基)胺基)吡啶并[3,4-d ]嗒

-7-基)氮雜環丁烷-3-醇 ¹ H NMR (400 MHz, DMSO-d₆ ) δ = 8.94 (s, 1H), 7.72 (d,J = 8.0 Hz, 1H), 7.49 (dd,J = 7.6, 18.8 Hz, 2H), 7.31 (t,J = 8.0 Hz, 1H), 7.08 (s, 1H), 5.71 (s, 1H), 5.62 (t,J = 6.8 Hz, 1H), 4.04 - 3.92 (m, 4H), 2.55 (s, 3H), 2.54 (s, 3H), 1.54 (d,J = 6.8 Hz, 3H), 1.49 (s, 3H)。LCMS [M+1]⁺ : 432.2。 12-22

(R )-1-(4-甲基-1-((1-(2-甲基-3-(三氟甲基)苯基)乙基)胺基)吡啶并[3,4-d ]嗒

-7-基)氮雜環丁烷-3-醇 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 14.76 (br s, 1H), 9.19 (s, 1H), 8.97 (br d,J = 3.6 Hz, 1H), 7.85 (d,J = 8.0 Hz, 1H), 7.60 - 7.53 (m, 2H), 7.35 (t,J = 8.0 Hz, 1H), 5.42 (br t,J = 6.8 Hz, 1H), 4.76 - 4.68 (m, 1H), 4.55 - 4.44 (m, 2H), 4.08 - 3.98 (m, 2H), 2.74 (s, 3H), 2.56 (s, 3H), 1.62 (d,J = 7.2 Hz, 3H)。LCMS [M+1]⁺ : 418.1。 12-23

3-((1R )-1-((7-(6-氧雜-3-氮雜雙環[3.1.1]庚-3-基)-4-甲基吡啶并[3,4-d ]嗒

-1-基)胺基)乙基)-2-甲基苯甲腈 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.04 (s, 1H), 8.14 (s, 1H), 7.73 (d,J = 7.6 Hz, 1H), 7.64 - 7.57 (m, 2H), 7.31 (t,J = 7.6 Hz, 1H), 7.26 (s, 1H), 5.56 - 5.52 m, 1H), 4.80 (d,J = 6.0 Hz, 2H), 3.91 - 3.87 (m, 2H), 3.74 - 3.68 (m, 2H), 3.20 (d,J = 8.4 Hz, 2H), 2.66 (s, 3H), 2.57 (s, 3H), 1.95 (d,J = 9.2 Hz, 1H), 1.55 (d,J = 7.2 Hz, 3H)。LCMS [M+1]⁺ : 401.3。 12-24

3-((R )-1-((7-((1R ,4R )-2-氧雜-5-氮雜雙環[2.2.1]庚-5-基)-4-甲基吡啶并[3,4-d ]嗒

-1-基)胺基)乙基)-2-甲基苯甲腈 甲酸鹽 ¹ H NMR (400 MHz, CD₃ OD)δ = 9.10 (s, 1H), 8.47 (s, 1H), 7.70 (d,J = 7.6 Hz, 1H), 7.52 (d,J = 7.6 Hz, 1H), 7.28 (t,J = 7.6 Hz, 1H), 7.20 (s, 1H), 5.49 - 5.43 (m, 1H), 5.24 (s, 1H), 4.85 - 4.83 (m, 1H), 4.83 (s, 2H), 3.96 (d,J = 7.6 Hz, 1H), 3.85 (d,J = 7.6 Hz, 1H), 3.69 (d,J = 10.4 Hz, 1H), 3.55 (d,J = 10.8 Hz, 1H), 2.71 (s, 3H), 2.71 (s, 3H), 2.09 (s, 2H), 1.63 (d,J = 7.2 Hz, 3H)。LCMS [M+1]⁺ : 401.3。 12-25

(R )-2-甲基-3-(1-((4-甲基-7-(哌

-1-基)吡啶并[3,4-d ]嗒

-1-基)胺基)乙基)苯甲腈 鹽酸鹽 ¹ H NMR (400 MHz, CD₃ OD) δ = 9.30 (s, 1H), 7.87 (s, 1H), 7.82 (d,J = 7.2 Hz, 1H), 7.55 (d,J = 6.8 Hz, 1H), 7.30 (t,J = 8.0 Hz, 1H), 7.34 - 7.26 (m, 1H), 5.44 (q,J = 6.8 Hz, 1H), 4.35 - 4.26 (m, 4H), 3.49 - 3.40 (m, 4H), 2.82 (s, 3H), 2.74 (s, 3H), 1.70 (d,J = 7.2 Hz, 3H)。LCMS [M+1]⁺ : 388.2。 12-26

4-甲基-N -((R )-1-(2-甲基-3-(三氟甲基)苯基)乙基)-7-((1R ,4R )-5-甲基-2,5-二氮雜雙環[2.2.2]辛-2-基)吡啶并[3,4-d ]嗒

-1-胺 甲酸鹽 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ= 8.94 (s, 1H), 8.17 (s, 1H), 7.73 (d,J = 8.0 Hz, 1H), 7.56 - 7.45 (m, 2H), 7.32 (t,J = 7.6 Hz, 1H), 7.11 (s, 1H), 5.70 - 5.58 (m, 1H), 4.88 - 4.69 (m, 1H), 3.86 (d,J = 11.2 Hz, 1H), 3.05 - 2.99 (m, 2H), 2.93 - 2.85 (m, 1H), 2.56 (s, 3H), 2.54 (s, 3H), 2.43 (s, 3H), 2.16 - 2.03 (m, 1H), 1.88 - 1.79 (m, 2H), 1.72 - 1.63 (m, 1H), 1.55 (d,J = 6.8 Hz, 3H)。LCMS [M+1]⁺ : 471.2。 12-27

3-((R )-1-((7-((S )-六氫吡

并[2,1-c][1,4]

-8(1H )-基)-4-甲基吡啶并[3,4-d ]嗒

-1-基)胺基)乙基)-2-甲基苯甲腈 ¹ H NMR (400 MHz, CD₃ OD)  δ = 9.02 (s, 1H), 7.72 (d,J = 7.6 Hz, 1H), 7.51 (dd, J = 1.2, 7.6 Hz, 1H), 7.34 (s, 1H), 7.27 (t,J = 8.0 Hz, 1H), 5.60 (q,J = 6.8 Hz, 1H), 4.63 (br d,J = 13.6 Hz, 1H), 4.42 (br d,J = 12.8 Hz, 1H), 3.94 - 3.83 (m, 2H), 3.75 (dt,J = 2.4, 11.6 Hz, 1H), 3.39 (t,J = 10.8 Hz, 1H), 3.18 (dt,J = 3.2, 12.8 Hz, 1H), 2.97 (br d,J = 11.6 Hz, 1H), 2.81 (br d,J = 11.6 Hz, 1H), 2.77 - 2.71 (m, 3H), 2.71 - 2.66 (m, 1H), 2.64 (s, 3H), 2.48 - 2.32 (m, 3H), 1.63 (d, J = 6.8 Hz, 3H)。LCMS [M+1]⁺ : 444.2。 12-28

(R )-3-(1-((7-(4-(二甲基胺基)哌啶-1-基)-4-甲基吡啶并[3,4-d ]嗒

-1-基)胺基)乙基)-2-甲基苯甲腈 鹽酸鹽 ¹ H NMR (400 MHz, CD₃ OD) δ = 9.25 (s, 1H), 7.77 (d,J = 8.0 Hz, 1H), 7.72 (s, 1H), 7.55 (d,J = 7.6 Hz, 1H), 7.33 - 7.27 (m, 1H), 5.43 (q,J = 6.8 Hz, 1H), 5.12 - 5.01 (m, 2H), 3.72 - 3.59 (m, 1H), 3.24 (br t,J = 12.4 Hz, 2H), 2.92 (s, 6H), 2.79 (s, 3H), 2.74 (s, 3H), 2.32 (br d,J = 11.6 Hz, 2H), 1.89 - 1.75 (m, 2H), 1.68 (d,J = 6.8 Hz, 3H)。LCMS [M+1]⁺ : 430.3。 12-29

(R )-3-(1-((7-(4-(氮雜環丁烷-1-基)哌啶-1-基)-4-甲基吡啶并[3,4-d ]嗒

-1-基)胺基)乙基)-2-甲基苯甲腈 鹽酸鹽 ¹ H NMR (400 MHz, DMSO-d₆ ) δ = 14.94 - 14.58 (m, 1H), 11.66 - 11.25 (m, 1H), 9.24 (s, 1H), 8.11 (s, 1H), 7.91 (d,J = 8.0 Hz, 1H), 7.65 (d,J = 7.6 Hz, 1H), 7.36 (t,J = 8.0 Hz, 1H), 5.33 (t,J = 6.8 Hz, 1H), 4.90 (br d,J = 13.2 Hz, 2H), 4.21 - 3.92 (m, 4H), 3.55 (br s, 1H), 3.18 (br t,J = 12.8 Hz, 2H), 2.74 (s, 3H), 2.67 (s, 3H), 2.44 - 2.19 (m, 2H), 2.08 (br d,J = 10 Hz, 2H), 1.64 (d,J = 6.8 Hz, 3H), 1.53 - 1.40 (m, 2H)。LCMS [M+1]⁺ : 442.3。 12-30

(R )-3-(1-((7-(3-羥基-3-甲基氮雜環丁烷-1-基)-4-甲基吡啶并[3,4-d ]嗒

-1-基)胺基)乙基)-2-甲基苯甲腈 ¹ H NMR (400 MHz, DMSO-d₆ ) δ = 14.80 (br s, 1H), 9.19 (s, 1H), 9.04 (br d,J = 3.6 Hz, 1H), 7.87 (d,J = 8.0 Hz, 1H), 7.69 - 7.59 (m, 2H), 7.39 - 7.31 (m, 1H), 5.37 - 5.24 (m, 1H), 4.21 - 4.05 (m, 4H), 2.74 (s, 3H), 2.66 (s, 3H), 1.62 (br d,J = 7.2 Hz, 3H), 1.49 (s, 3H)。LCMS [M+1]⁺ : 389.2。 12-31

7-(3-氧雜-8-氮雜雙環[3.2.1]辛-8-基)-4-甲基-N -((R )-1-(2-甲基-3-(三氟甲基)苯基)乙基)吡啶并[3,4-d ]嗒

-1-胺 鹽酸鹽 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 14.65 (s, 1H), 9.26 (s, 1H), 8.88 (s, 1H), 7.88 (s, 1H), 7.82 (d,J = 8.0 Hz, 1H), 7.56 (d,J = 7.6 Hz, 1H), 7.36 (t,J = 7.6 Hz, 1H), 5.47 - 5.37 (m, 1H), 4.94 (s, 2H), 3.79 - 3.61 (m, 4H), 2.73 (s, 3H), 2.56 (s, 3H), 2.18 - 1.94 (m, 4H), 1.62 (d,J = 6.8 Hz, 3H)。LCMS [M+1]⁺ : 458.1。 12-32

(R )-2-(4-甲基-1-((1-(2-甲基-3-(三氟甲基)苯基)乙基)胺基)吡啶并[3,4-d]嗒

-7-基)-2,6-二氮雜螺[3.4]辛-5-酮 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.24 (s, 1H), 8.78 (s, 1H), 7.94 (s, 1H), 7.76 (d,J = 7.9 Hz, 1H), 7.55 (d,J = 7.8 Hz, 1H), 7.49 (s, 1H), 7.34 (t,J = 7.8 Hz, 1H), 5.46 - 5.35 (m, 1H), 4.40 - 4.14 (m, 5H), 3.23 (t,J = 6.7 Hz, 2H), 2.72 (s, 3H), 2.54 (s, 3H), 1.59 (d,J = 6.9 Hz, 4H)。LCMS [M+1]⁺ : 471.1。 12-33

(R )-7-(4-(氮雜環丁烷-1-基)哌啶-1-基)-4-甲基-N -(1-(2-甲基-3-(三氟甲基)苯基)乙基)吡啶并[3,4-d ]嗒

-1-胺 ¹ H NMR (400 MHz, 甲醇-d ₄ ) δ 9.23 (s, 1H), 7.77 - 7.70 (m, 2H), 7.53 (d,J = 7.8 Hz, 1H), 7.29 (t,J = 7.8 Hz, 1H), 5.51 (q,J = 6.9 Hz, 1H), 5.04 - 4.95 (m, 2H), 4.34 - 4.15 (m, 4H), 3.67 (d,J = 12.0 Hz, 1H), 3.25 (t,J = 13.1 Hz, 2H), 2.78 (s, 3H), 2.70 - 2.59 (m, 4H), 2.47 - 2.35 (m, 1H), 2.23 (d,J = 12.5 Hz, 2H), 1.68 (d,J = 6.9 Hz, 3H), 1.62 - 1.48 (m, 2H)。LCMS [M+1]⁺ : 485.2。 12-34

(R )-3-(1-((7-(4,4-二氟哌啶-1-基)-4-甲基吡啶并[3,4-d ]嗒

-1-基)胺基)乙基)-2-甲基苯甲腈 ¹ H NMR (400 MHz, 甲醇-d ₄ ) δ 9.06 (d,J = 0.8 Hz, 1H), 7.73 (dd,J = 7.9, 1.3 Hz, 1H), 7.52 (dd,J = 7.7, 1.3 Hz, 1H), 7.48 (d,J = 0.9 Hz, 1H), 7.28 (t,J = 7.8 Hz, 1H), 5.58 (q,J = 7.0 Hz, 1H), 4.03 (t,J = 5.8 Hz, 5H), 2.75 (s, 3H), 2.66 (s, 3H), 2.11 (ddt,J = 19.0, 13.5, 5.7 Hz, 5H), 1.64 (d,J = 7.0 Hz, 3H)。LCMS [M+1]⁺ : 423.2。 12-35

(R )-2-甲基-3-(1-((4-甲基-7-(6-甲基-5-側氧基-2,6-二氮雜螺[3.4]辛-2-基)吡啶并[3,4-d ]嗒

-1-基)胺基)乙基)苯甲腈 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.96 (s, 1H), 7.72 (d,J = 7.8 Hz, 1H), 7.60 (dd,J = 7.6, 1.3 Hz, 1H), 7.49 (d,J = 6.8 Hz, 1H), 7.31 (t,J = 7.8 Hz, 1H), 7.09 (s, 1H), 5.52 (q,J = 7.0 Hz, 1H), 4.19 (dd,J = 8.3, 5.1 Hz, 2H), 4.05 (dd,J = 8.0, 1.7 Hz, 2H), 2.79 (s, 3H), 2.68 - 2.64 (m, 4H), 2.55 (s, 3H), 2.43 (t,J = 6.8 Hz, 2H), 2.33 (p,J = 1.8 Hz, 1H), 1.53 (d,J = 7.0 Hz, 3H)。LCMS [M+1]⁺ : 442.2。 12-36

(R )-2-甲基-3-(1-((4-甲基-7-(4-(1-甲基-1H -吡唑-4-基)哌

-1-基)吡啶并[3,4-d ]嗒

-1-基)胺基)乙基)苯甲腈 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.00 (s, 1H), 7.71 (dd,J = 8.0, 1.4 Hz, 1H), 7.61 (dd,J = 7.6, 1.3 Hz, 1H), 7.55 (d,J = 6.8 Hz, 1H), 7.46 (s, 1H), 7.36 (s, 1H), 7.32 (t,J = 7.8 Hz, 1H), 7.24 (d,J = 0.9 Hz, 1H), 5.54 (q,J = 6.7 Hz, 1H), 3.85 (t,J = 5.2 Hz, 4H), 3.75 (s, 3H), 3.01 (t,J = 5.2 Hz, 4H), 2.65 (s, 3H), 2.55 (s, 3H), 1.55 (d,J = 7.0 Hz, 3H)。LCMS [M+1]⁺ : 468.3。 12-37

(R )-7-(3-甲氧基-3-甲基氮雜環丁烷-1-基)-4-甲基-N -(1-(2-甲基-3-(三氟甲基)苯基)乙基)吡啶并[3,4-d ]嗒

-1-胺 ¹ H NMR (400 MHz, CDCl₃ ) δ 8.85 (s, 1H), 8.54 (s, 1H), 7.65 (d,J = 7.9 Hz, 1H), 7.49 (d,J = 7.8 Hz, 1H), 7.18 (t,J = 7.8 Hz, 1H), 6.75 (s, 1H), 5.57 (q,J = 6.8 Hz, 1H), 4.25 - 4.16 (m, 2H), 4.09 - 4.00 (m, 2H), 3.32 (s, 3H), 2.64 (s, 3H), 2.52 (s, 3H), 1.64 (d,J = 6.8 Hz, 3H), 1.59 (s, 3H)。LCMS [M+1]⁺ : 446.4。 12-38

(R )-7-(氮雜環丁烷-1-基)-4-甲基-N -(1-(2-甲基-3-(三氟甲基)苯基)乙基)吡啶并[3,4-d ]嗒

-1-胺 鹽酸鹽 ¹ H NMR (400 MHz, CD₃ OD) δ = 9.15 (s, 1H), 7.68 (d,J = 7.9 Hz, 1H), 7.54 (d,J = 7.8 Hz, 1H), 7.29 (t,J = 7.8 Hz, 1H), 7.16 (s, 1H), 5.49 (q,J = 7.0 Hz, 1H), 4.37 (t,J = 7.7 Hz, 5H), 2.75 (s, 3H), 2.68 - 2.50 (m, 5H), 1.65 (d,J = 7.0 Hz, 3H)。LCMS [M+1]⁺ : 402.2。 12-39

(R )-(3-甲基-1-(4-甲基-1-((1-(2-甲基-3-(三氟甲基)苯基)乙基)胺基)吡啶并[3,4-d ]嗒

-7-基)氮雜環丁烷-3-基)甲醇 ¹ H NMR (400 MHz, CD₃ OD) δ = 9.15 (d,J = 0.8 Hz, 1H), 7.69 - 7.65 (m, 1H), 7.55 - 7.51 (m, 1H), 7.29 (t,J = 7.9 Hz, 1H), 7.17 (d,J = 0.8 Hz, 1H), 5.49 (q,J = 6.9 Hz, 1H), 4.24 - 4.17 (m, 2H), 3.93 (dd,J = 9.6, 3.7 Hz, 2H), 3.64 (s, 2H), 2.75 (s, 3H), 2.61 (d,J = 1.6 Hz, 3H), 1.65 (d,J = 7.0 Hz, 3H), 1.41 (s, 3H)。LCMS [M+1]⁺ : 446.2。 12-40

2-甲基-3-((R )-1-((4-甲基-7-((1R ,4R )-5-甲基-2,5-二氮雜雙環[2.2.2]辛-2-基)吡啶并[3,4-d ]嗒

-1-基)胺基)乙基)苯甲腈 甲酸鹽 ¹ H NMR (400 MHz, DMSO-d₆ ) δ = 8.94 (s, 1H), 8.16 (s, 1H), 7.72 (d, J = 7.6 Hz, 1H), 7.62 (d, J = 7.6 Hz, 1H), 7.55 - 7.50 (m, 1H), 7.32 (t, J = 7.6 Hz, 1H), 7.09 (s, 1H), 5.55 - 5.51 (m, 1H), 4.81- 4.76 (m, 1H), 3.86 - 3.83 (m, 1H), 3.47 - 3.44 (m, 1H), 3.02 - 3.00 (m, 2H), 2.90 - 2.85 (m, 1H), 2.66 (s, 3H), 2.54 (s, 3H), 2.41 (s, 3H), 2.12 - 2.07 (m, 1H), 1.90 - 1.82 (m, 2H), 1.71 - 1.64 (m, 1H), 1.54 (d, J = 6.8 Hz, 3H)。LCMS [M+1]⁺ : 428.4。 12-41

(R )-4-甲基-N -(1-(2-甲基吡啶-3-基)乙基)-7-

啉基吡啶并[3,4-d ]嗒

-1-胺 ¹ H NMR (400 MHz, CD₃ OD) δ 9.02 (d,J = 0.9 Hz, 1H), 8.22 (dd,J = 5.0, 1.7 Hz, 1H), 7.83 (dd,J = 7.9, 1.7 Hz, 1H), 7.31 (d,J = 1.0 Hz, 1H), 7.18 (dd,J = 7.9, 4.9 Hz, 1H), 5.59 - 5.53 (m, 1H), 3.86 - 3.81 (m, 4H), 3.79 - 3.73 (m, 4H), 2.72 (s, 3H), 2.63 (s, 3H), 1.63 (d,J = 7.0 Hz, 3H)。LCMS [M+1]⁺ : 365.3。 12-42

N-((R )-1-(3-(二氟甲基)-2-甲基苯基)乙基)-7-((S )-六氫吡

并[2,1-c ][1,4]

-8(1H )-基)-4-甲基吡啶并[3,4-d ]嗒

-1-胺 甲酸鹽    ¹ H NMR (400 MHz, DMSO-d ₆ ):δ = 8.96 (s, 1H), 8.19 (s, 1H), 7.58 (d,J = 7.6 Hz, 1H), 7.45 (d,J = 7.2 Hz, 1H), 7.40 (s, 1H), 7.39 - 7.33 (m, 1H), 7.29 - 7.05 (m, 2H), 5.65 - 5.61 (m, 1H), 4.51 - 4.26 (m, 2H), 3.83 - 3.77 (m, 2H), 3.58 - 3.56 (m, 1H), 3.23 (t,J = 10.8, 1H), 3.06 (dt,J = 12.4, 2.8 Hz, 1H), 2.91 (d,J = 11.2 Hz, 1H), 2.72 (d,J = 11.2 Hz, 1H), 2.61 - 2.56 (m, 1H), 2.54 (s, 3H), 2.48 (s, 3H), 2.29 - 2.24 (m, 3H), 1.53 (d,J = 6.8 Hz, 3H)。LCMS [M+1]⁺ : 469.2。 12-43

(R )-3-(1-((7-(3-(二甲基胺基)-3-甲基氮雜環丁烷-1-基)-4-甲基吡啶并[3,4-d ]嗒

-1-基)胺基)乙基)-2-甲基苯甲腈 鹽酸鹽 ¹ H NMR (400 MHz, CD₃ OD) δ = 9.26 (s, 1H), 7.79 (d,J = 8.0 Hz, 1H), 7.55 (d,J = 7.6 Hz, 1H), 7.49 (s, 1H), 7.30 (t,J = 8.0 Hz, 1H), 5.43 (q,J = 7.2 Hz, 1H), 4.64 (br dd,J = 4.4, 10.4 Hz, 2H), 4.35 (dd,J = 4.4, 10.4 Hz, 2H), 2.94 (s, 6H), 2.81 (s, 3H), 2.73 (s, 3H), 1.82 (s, 3H), 1.69 (d,J = 6.8 Hz, 3H)。LCMS [M+1]⁺ : 416.2。 12-44

(R)-2-甲基-3-(1-((4-甲基-7-(4-甲基哌

-1-基)吡啶并[3,4-d]嗒

-1-基)胺基)乙基)苯甲腈 ¹ H NMR (400 MHz, CD₃ OD) δ = 9.02 (s, 1H), 7.73 (d,J = 7.6 Hz, 1H), 7.51 (d,J = 8.0 Hz, 1H), 7.36 (s, 1H), 7.27 (t,J = 8.0 Hz, 1H), 5.59 (q,J = 7.2 Hz, 1H), 3.85 (s, 4H), 2.75 (s, 3H), 2.68 - 2.56 (m, 7H), 2.40 (s, 3H), 1.63 (d,J = 6.8 Hz, 3H)。LCMS [M+1]⁺ : 402.3。 12-45

(R )-3-(1-((7-(二甲基胺基)-4-甲基吡啶并[3,4-d ]嗒

-1-基)胺基)乙基)-2-甲基苯甲腈 ¹ H NMR (400 MHz, CD₃ OD) δ = 8.96 (s, 1H), 7.72 (d,J = 8.0 Hz, 1H), 7.49 (d,J = 7.6 Hz, 1H), 7.25 (t,J = 7.6 Hz, 1H), 7.12 (s, 1H), 5.58 (q,J = 7.2 Hz, 1H), 3.27 (s, 6H), 2.73 (s, 3H), 2.60 (br s, 3H), 1.62 (d,J = 6.8 Hz, 3H)。LCMS [M+1]⁺ : 347.2。 12-46

(R )-3-(1-((7-(4-(二甲基胺基)-4-甲基哌啶-1-基)-4-甲基吡啶并[3,4-d ]嗒

-1-基)胺基)乙基)-2-甲基苯甲腈 ¹ H NMR (400 MHz, CD₃ OD) δ = 8.99 (s, 1H), 7.73 (d,J = 7.6 Hz, 1H), 7.51 (d,J = 7.6 Hz, 1H), 7.33 (s, 1H), 7.27 (t,J = 7.6 Hz, 1H), 5.60 (q,J = 6.8 Hz, 1H), 4.27 (br d,J = 13.2 Hz, 2H), 3.45 (ddd,J = 4.4, 8.8, 13.2 Hz, 2H), 2.75 (s, 3H), 2.63 (s, 3H), 2.31 (s, 6H), 1.85 - 1.71 (m, 4H), 1.63 (d,J = 7.2 Hz, 3H), 1.15 (s, 3H)。LCMS [M+1]⁺ : 444.5。 12-47

(R )-1-(1-((1-(2,4-二氟苯基)乙基)胺基)-4-甲基吡啶并[3,4-d ]嗒

-7-基)-3-甲基氮雜環丁烷-3-醇 ¹ H NMR (400 MHz, DMSO-d ₆ ): δ = 8.95 (s, 1H), 7.44 - 7.38 (m, 1H), 7.36 (d,J = 7.6 Hz, 1H), 7.23 - 7.12 (m, 1H), 7.06 (s, 1H), 7.01-6.93 (m, 1H), 5.71 (s, 1H), 5.62-5.52 (m, 1H), 4.05 - 3.90 (m, 4H), 2.54 (s, 3H), 1.55 (d,J = 7.2 Hz, 3H), 1.49 (s, 3H)。LCMS [M+1]⁺ : 386.1。 12-48

N -((R )-1-(2,4-二氟苯基)乙基)-7-((S )-六氫吡

并[2,1-c ][1,4]

-8(1H )-基)-4-甲基吡啶并[3,4-d ]嗒

-1-胺 甲酸鹽 ¹ H NMR (400 MHz, DMSO-d ₆ ): δ = 8.99 (s, 1H), 8.15 (s, 1H), 7.47 - 7.31 (m, 3H), 7.25-7.12 (m, 1H), 7.04 - 6.91 (m, 1H), 5.59 (t,J = 6.8 Hz, 1H), 4.49-4.31 (m, 2H), 3.88-3.74 (m, 2H), 3.61-3.54 (m, 1H), 3.24-3.21 (m, 1H), 3.12-3.04 (m, 1H), 2.92 (d,J = 10.8 Hz, 1H), 2.73 (d,J = 11.6 Hz, 1H), 2.63 - 2.57 (m, 1H), 2.57 - 2.53 (m, 3H), 2.29 - 2.15 (m, 3H), 1.57 (d,J = 7.2 Hz, 3H)。LCMS [M+1]⁺ : 441.4。 12-49

(R )-N -(1-(2,4-二氟苯基)乙基)-7-(3-(二甲基胺基)-3-甲基氮雜環丁烷-1-基)-4-甲基吡啶并[3,4-d ]嗒

-1-胺 甲酸鹽 ¹ H NMR (400 MHz, DMSO-d ₆ ): δ = 8.95 (s, 1H), 8.16 (s, 1H), 7.45 - 7.32 (m, 2H), 7.22 -7.14 (m, 1H), 7.08 (s, 1H), 7.01 - 6.93 (m, 1H), 5.57 (t,J = 6.8 Hz, 1H), 3.93 - 3.86 (m, 2H), 3.79 (d,J = 8.0 Hz, 2H), 2.55 (s, 3H), 2.15 (s, 6H), 1.56 (d,J = 7.2 Hz, 3H), 1.32 (s, 3H)。LCMS [M+1]⁺ : 413.4。 12-50

(R )-N -(1-(2-氟-3-(三氟甲基)苯基)乙基)-4-甲基-7-

啉基吡啶并[3,4-d ]嗒

-1-胺 ¹ H NMR (400 MHz, CD₃ OD) δ = 9.03 (d,J = 0.8 Hz, 1H), 7.65 (t,J = 6.8 Hz, 1H), 7.51 (t,J = 7.2 Hz, 1H), 7.37 (s, 1H), 7.21 (t,J = 7.6 Hz, 1H), 5.68 (q,J = 7.2 Hz, 1H), 3.88 - 3.83 (m, 4H), 3.81 - 3.76 (m, 4H), 2.62 (s, 3H), 1.68 (d,J = 7.2 Hz, 3H)。LCMS [M+1]⁺ : 436.2。 12-51

(R )-2-甲基-3-(1-((4-甲基-7-(6-甲基-2,6-二氮雜螺[3.4]辛-2-基)吡啶并[3,4-d ]嗒

-1-基)胺基)乙基)苯甲腈 ¹ H NMR (400 MHz, CD₃ OD) δ = 8.92 (s, 1H), 7.70 (d,J = 8.0 Hz, 1H), 7.49 (d,J = 8.0 Hz, 1H), 7.29 - 7.21 (m, 1H), 7.00 (s, 1H), 5.57 (q,J = 6.8 Hz, 1H), 4.21 - 4.14 (m, 2H), 4.14 - 4.06 (m, 2H), 2.88 (s, 2H), 2.75 (s, 3H), 2.69 (t,J = 7.2 Hz, 2H), 2.61 (s, 3H), 2.41 (s, 3H), 2.25 (t,J = 7.2 Hz, 2H), 1.61 (d,J = 7.2 Hz, 3H)。LCMS [M+1]⁺ : 428.2。 12-52

(R )-3-(1-((7-(4-乙基哌

-1-基)-4-甲基吡啶并[3,4-d ]嗒

-1-基)胺基)乙基)-2-甲基苯甲腈 ¹ H NMR (400 MHz, CD₃ OD) δ = 9.30 (s, 1H), 7.91 (s, 1H), 7.83 (d,J = 7.6 Hz, 1H), 7.55 (d,J = 7.6 Hz, 1H), 7.30 (t,J = 8.0 Hz, 1H), 5.44 (q,J = 6.8 Hz, 1H), 5.08 (br d,J = 14.4 Hz, 2H), 3.80 (br d,J = 12.0 Hz, 2H), 3.63 (br t,J = 12.8 Hz, 2H), 3.33 (s, 2H), 3.24 (br s, 2H), 2.82 (s, 3H), 2.74 (s, 3H), 1.70 (d,J = 6.8 Hz, 3H), 1.45 (t,J = 7.2 Hz, 3H)。LCMS [M+1]⁺ : 416.2。 12-53

(R )-3-(1-((7-(4-羥基-4-甲基哌啶-1-基)-4-甲基吡啶并[3,4-d ]嗒

-1-基)胺基)乙基)-2-甲基苯甲腈 ¹ H NMR (400 MHz, CD₃ OD) δ = 8.95 (s, 1H), 7.70 (d,J = 7.6 Hz, 1H), 7.48 (d,J = 6.8 Hz, 1H), 7.31 (s, 1H), 7.24 (t,J = 8.0 Hz, 1H), 5.61 - 5.49 (m, 1H), 4.23 - 4.13 (m, 2H), 3.63 - 3.52 (m, 2H), 2.72 (s, 3H), 2.59 (s, 3H), 1.73 - 1.64 (m, 4H), 1.60 (d,J = 6.8 Hz, 3H), 1.28 (s, 3H)。LCMS [M+1]⁺ : 417.3。 12-54

(R )-3-(1-((7-(3-(二甲基胺基)氮雜環丁烷-1-基)-4-甲基吡啶并[3,4-d ]嗒

-1-基)胺基)乙基)-2-甲基苯甲腈 鹽酸鹽 ¹ H NMR (400 MHz, CD₃ OD) δ = 9.26 (s, 1H), 7.80 (d,J = 7.2 Hz, 1H), 7.57 - 7.52 (m, 1H), 7.50 (s, 1H), 7.30 (t,J = 8.0 Hz, 1H), 5.43 (q,J = 6.8 Hz, 1H), 4.77 - 4.63 (m, 2H), 4.62 - 4.51 (m, 2H), 4.44 (tt,J = 4.8, 7.6 Hz, 1H), 3.00 (s, 6H), 2.81 (s, 3H), 2.73 (s, 3H), 1.69 (d,J = 6.8 Hz, 3H)。LCMS [M+1]⁺ :402.2。 12-55

(R )-3-(1-((7-(3-甲氧基-3-甲基氮雜環丁烷-1-基)-4-甲基吡啶并[3,4-d ]嗒

-1-基)胺基)乙基)-2-甲基苯甲腈 ¹ H NMR (400 MHz, CD₃ OD) δ = 9.18 (s, 1H), 7.71 (d,J = 7.2 Hz, 1H), 7.55 (d,J = 6.8 Hz, 1H), 7.30 (t,J = 7.6 Hz, 1H), 7.21 (s, 1H), 5.40 (q,J = 6.8 Hz, 1H), 4.25 (dd,J = 2.8, 9.8 Hz, 2H), 4.13 (dd,J = 1.6, 10.0 Hz, 2H), 3.35 (s, 3H), 2.77 (s, 3H), 2.73 (s, 3H), 1.65 (d,J = 7.2 Hz, 3H), 1.62 (s, 3H)。LCMS [M+1]⁺ : 403.2。 12-56

(R )-1-(1-((1-(2,3-二氟苯基)乙基)胺基)-4-甲基吡啶并[3,4-d ]嗒

-7-基)-3-甲基氮雜環丁烷-3-醇 ¹ H NMR (400 MHz, DMSO-d ₆ )δ = 8.95 (s, 1H), 7.42 (d,J = 6.8 Hz, 1H), 7.27 - 7.17 (m, 2H), 7.14 - 7.05 (m, 2H), 5.71 (s, 1H), 5.65 - 5.58 (m, 1H), 4.05 - 3.94 (m, 4H), 2.55 (s, 3H), 1.60 (d,J = 6.8 Hz, 3H), 1.49 (s, 3H)。LCMS [M+1]⁺ : 386.0。 12-57

(R )-1-(1-((1-(4-氟-2-甲基苯基)乙基)胺基)-4-甲基吡啶并[3,4-d ]嗒

-7-基)-3-甲基氮雜環丁烷-3-醇 ¹ H NMR (400 MHz, CD₃ OD) δ = 8.92 (s, 1H), 7.41 (dd,J = 6.0, 8.4 Hz, 1H), 7.01 (s, 1H), 6.90 - 6.77 (m, 2H), 5.56 (q,J = 6.8 Hz, 1H), 4.12 - 3.98 (m, 4H), 2.63 (s, 3H), 2.47 (s, 3H), 1.62 - 1.55 (m, 6H)。LCMS [M+1]⁺ : 382.1。 12-58

7-(6-氧雜-3-氮雜雙環[3.1.1]庚-3-基)-N -((R )-1-(2,4-二氟苯基)乙基)-4-甲基吡啶并[3,4-d ]嗒

-1-胺 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.05 (s, 1H), 7.49 - 7.38 (m, 3H), 7.26 (s, 2H), 7.21 - 7.15 (m, 1H), 6.98 (t,J = 8.7 Hz, 1H), 5.62 (t,J = 7.0 Hz, 1H), 4.84 - 4.78 (m, 2H), 3.93 - 3.86 (m, 2H), 3.79 - 3.69 (m, 2H), 3.24 - 3.17 (m, 1H), 2.58 (s, 3H), 1.95 (d,J = 8.8 Hz, 1H), 1.58 (d,J = 7.1 Hz, 3H)。LCMS [M+1]⁺ : 398.1。 12-59

(R )-N-(1-(3-(二氟甲基)-2-甲基苯基)乙基)-4-甲基-7-(4-(1-甲基-1H -吡唑-4-基)哌

-1-基)吡啶并[3,4-d ]嗒

-1-胺 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.99 (s, 1H), 7.62 - 7.18 (m, 7H), 5.64 (t,J = 6.9 Hz, 1H), 3.88 - 3.81 (m, 4H), 3.75 (s, 3H), 3.04 - 2.97 (m, 4H), 2.55 (s, 3H), 1.54 (d,J = 6.9 Hz, 3H)。 LCMS [M+1]⁺ : 493.3。 12-60

N -((R )-1-(2-氟-3-(三氟甲基)苯基)乙基)-4-甲基-7-((1R ,4R )-5-甲基-2,5-二氮雜雙環[2.2.2]辛-2-基)吡啶并[3,4-d ]嗒

-1-胺 甲酸鹽 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.94 (s, 1H), 7.69 (t,J = 7.2 Hz, 1H), 7.61 (t,J = 7.2 Hz, 1H), 7.47 (d,J = 7.0 Hz, 1H), 7.31 (t,J = 7.8 Hz, 1H), 7.11 (s, 1H), 5.70 - 5.59 (m, 1H), 3.84 (d,J = 11.2 Hz, 1H), 3.45 (d,J = 11.1 Hz, 1H), 3.00 - 2.77 (m, 4H), 2.37 (s, 3H), 2.13 - 1.96 (m, 2H), 1.87 - 1.79 (m, 2H), 1.61 (d,J = 7.0 Hz, 3H)。LCMS [M+1]⁺ : 475.0。 12-61

(R )-1-(1-((1-(2-氟-3-(三氟甲基)苯基)乙基)胺基)-4-甲基吡啶并[3,4-d ]嗒

-7-基)-3-甲基氮雜環丁烷-3-醇 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.96 (s, 1H), 7.69 (t,J = 7.3 Hz, 1H), 7.61 (t,J = 7.2 Hz, 1H), 7.48 (d,J = 7.0 Hz, 1H), 7.30 (t,J = 7.8 Hz, 1H), 7.08 (s, 1H), 5.67 - 5.59 (m, 1H), 4.05 - 3.93 (m, 4H), 2.54 (s, 3H), 1.60 (d,J = 7.0 Hz, 3H), 1.50 (s, 3H)。 LCMS [M+1]⁺ : 436.1。 12-62

(R )-7-(3-(二甲基胺基)-3-甲基氮雜環丁烷-1-基)-N -(1-(2-氟-3-(三氟甲基)苯基)乙基)-4-甲基吡啶并[3,4-d ]嗒

-1-胺 甲酸鹽 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.08 (s, 1H), 7.90 (s, 1H), 7.73 (t,J = 7.4 Hz, 1H), 7.64 (t,J = 7.3 Hz, 1H), 7.33 (t,J = 7.8 Hz, 1H), 7.21 (s, 1H), 5.63 - 5.54 (m, 1H), 4.06 (d,J = 9.0 Hz, 2H), 3.91 (d,J = 8.8 Hz, 2H), 2.62 (s, 3H), 2.29 (s, 6H), 1.63 (d,J = 7.0 Hz, 3H), 1.41 (s, 3H)。 LCMS [M+1]⁺ : 463.3。 12-63

N -((R )-1-(2-氟-3-(三氟甲基)苯基)乙基)-7-((S )-六氫吡

并[2,1-c ][1,4]

-8(1H )-基)-4-甲基吡啶并[3,4-d ]嗒

-1-胺 ¹ H NMR (400 MHz, 甲醇-d ₄ ) δ 9.02 (s, 1H), 7.65 (t,J = 7.4 Hz, 1H), 7.51 (t,J = 7.2 Hz, 1H), 7.37 (s, 1H), 7.21 (t,J = 7.8 Hz, 1H), 5.68 (q,J = 7.1 Hz, 1H), 4.63 (d,J = 13.3 Hz, 1H), 4.43 (d,J = 12.8 Hz, 1H), 3.93 - 3.71 (m, 3H), 3.38 (t,J = 10.7 Hz, 1H), 3.24 - 3.11 (m, 1H), 2.97 (d,J = 11.4 Hz, 1H), 2.80 (d,J = 11.6 Hz, 1H), 2.71 (t,J = 11.7 Hz, 1H), 2.62 (s, 3H), 2.47 - 2.33 (m, 3H), 1.68 (d,J = 7.0 Hz, 3H)。LCMS [M+1]⁺ : 491.4。 12-64

(R )-7-(4-(二甲基胺基)哌啶-1-基)-N -(1-(2-氟-3-(三氟甲基)苯基)乙基)-4-甲基吡啶并[3,4-d ]嗒

-1-胺 甲酸鹽 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.99 (s, 1H), 7.70 (t,J = 7.4 Hz, 1H), 7.62 (t,J = 7.3 Hz, 1H), 7.57 (d,J = 6.8 Hz, 1H), 7.47 (s, 1H), 7.31 (t,J = 7.7 Hz, 1H), 5.69 - 5.60 (m, 1H), 4.64 (d,J = 13.2 Hz, 2H), 3.02 (t,J = 12.6 Hz, 2H), 2.88 - 2.75 (m, 1H), 2.55 (s, 3H), 2.41 (s, 6H), 2.04 - 1.94 (m, 2H), 1.62 (d,J = 7.0 Hz, 3H), 1.49 (q,J = 12.4 Hz, 2H)。LCMS [M+1]⁺ : 477.3。 12-65

(R )-N -(1-(2-氟-3-(三氟甲基)苯基)乙基)-4-甲基-7-(哌

-1-基)吡啶并[3,4-d ]嗒

-1-胺 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.02 (s, 1H), 7.70 (t,J = 7.4 Hz, 1H), 7.62 (t,J = 7.2 Hz, 1H), 7.56 (s, 1H), 7.48 (s, 1H), 7.31 (t,J = 7.8 Hz, 1H), 5.69 - 5.60 (m, 1H), 3.85 - 3.77 (m, 4H), 3.10 - 3.02 (m, 4H), 2.56 (s, 3H), 1.62 (d,J = 7.0 Hz, 3H)。LCMS [M+1]⁺ : 435.3。 12-66

(R )-7-(3-(二甲基胺基)氮雜環丁烷-1-基)-N -(1-(2-氟-3-(三氟甲基)苯基)乙基)-4-甲基吡啶并[3,4-d ]嗒

-1-胺 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.96 (s, 1H), 7.70 (t,J = 7.4 Hz, 1H), 7.61 (t,J = 7.3 Hz, 1H), 7.48 (d,J = 6.9 Hz, 1H), 7.30 (t,J = 7.8 Hz, 1H), 7.10 (s, 1H), 5.68 - 5.59 (m, 1H), 4.21 - 4.13 (m, 2H), 3.94 - 3.86 (m, 2H), 2.55 (s, 2H), 2.16 (s, 5H), 1.60 (d,J = 7.0 Hz, 3H)。LCMS [M+1]⁺ : 449.3。 12-67

(R )-N -(1-(2-氟-3-(三氟甲基)苯基)乙基)-4-甲基-7-(4-甲基哌

-1-基)吡啶并[3,4-d ]嗒

-1-胺 ¹ H NMR (400 MHz, CD₃ OD) δ = 9.12 (s, 1H), 8.47 (s, 1H), 7.68 (t,J = 7.3 Hz, 1H), 7.54 (t,J = 7.3 Hz, 1H), 7.47 (s, 1H), 7.24 (t,J = 7.8 Hz, 1H), 5.61 (q,J = 7.0 Hz, 1H), 3.95 (t,J = 5.2 Hz, 4H), 2.69 (d,J = 2.9 Hz, 7H), 2.44 (s, 3H), 1.70 (d,J = 7.0 Hz, 3H)。LCMS [M+1]⁺ : 449.0。 12-68

(R )-7-(4-乙基哌

-1-基)-N -(1-(2-氟-3-(三氟甲基)苯基)乙基)-4-甲基吡啶并[3,4-d ]嗒

-1-胺 ¹ H NMR (400 MHz, CD₃ OD) δ =  9.10 (s, 1H), 7.69 (t,J = 7.4 Hz, 1H), 7.55 (t,J = 7.2 Hz, 1H), 7.44 (s, 1H), 7.25 (t,J = 7.8 Hz, 1H), 5.66 (q,J = 7.0 Hz, 1H), 3.93 (t,J = 5.2 Hz, 4H), 2.73 (t,J = 5.2 Hz, 4H), 2.68 (s, 3H), 2.61 (q,J = 7.2 Hz, 2H), 1.71 (d,J = 7.0 Hz, 3H), 1.22 (t,J = 7.2 Hz, 3H)。LCMS [M+1]⁺ : 463.0。 12-69

3-((R )-1-((7-((S )-3-(二甲基胺基)吡咯啶-1-基)-4-甲基吡啶并[3,4-d ]嗒

-1-基)胺基)乙基)-2-甲基苯甲腈 ¹ H NMR (400 MHz, CD₃ OD) δ 8.95 (d,J = 0.8 Hz, 1H), 7.71 (dd,J = 8.0, 1.4 Hz, 1H), 7.50 (d,J = 1.4 Hz, 0H), 7.24 (t,J = 7.8 Hz, 1H), 7.01 (s, 1H), 5.58 (q,J = 6.9 Hz, 1H), 3.97 - 3.83 (m, 3H), 3.61 - 3.49 (m, 1H), 3.41 - 3.34 (m, 1H), 3.31 (s, 9H), 3.04 - 2.97 (m, 1H), 2.72 (s, 3H), 2.61 (s, 3H), 2.43 - 2.32 (m, 7H), 2.05 - 1.93 (m, 1H), 1.62 (d,J = 6.9 Hz, 4H)。LCMS [M+1]⁺ : 416.3。 12-70

3-((R )-1-((7-((1R ,4R )-5-(2-甲氧基乙基)-2,5-二氮雜雙環[2.2.2]辛-2-基)-4-甲基吡啶并[3,4-d ]嗒

-1-基)胺基)乙基)-2-甲基苯甲腈 ¹ H NMR (400 MHz, CD₃ OD) δ = 9.17 - 9.14 (m, 1H), 7.74 (dd,J = 7.8, 1.3 Hz, 1H), 7.54 (dd,J = 7.7, 1.3 Hz, 1H), 7.31 - 7.25 (m, 2H), 5.47 (q,J = 6.9 Hz, 1H), 5.09 (s, 1H), 4.09 (d,J = 12.4 Hz, 1H), 3.71 (d,J = 12.4 Hz, 1H), 3.64 (t,J = 5.3 Hz, 2H), 3.57 (br s, 2H), 3.39 (s, 3H), 3.23 - 3.08 (m, 3H), 2.33 (d,J = 9.1 Hz, 1H), 2.03 (t,J = 8.3 Hz, 2H), 1.93 - 1.83 (m, 1H), 1.66 (d,J = 7.0 Hz, 3H)。LCMS [M+1]⁺ : 472.3。 12-71

(R )-2-甲基-3-(1-((4-甲基-7-(6-氧雜-2-氮雜螺[3.4]辛-2-基)吡啶并[3,4-d ]嗒

-1-基)胺基)乙基)苯甲腈 鹽酸鹽 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ  = 14.73 (s, 1H), 9.24 (d,J = 2.7 Hz, 1H), 8.88 (s, 1H), 7.80 (d,J = 8.2 Hz, 1H), 7.66 (d,J = 7.6 Hz, 1H), 7.52 (s, 1H), 7.41 - 7.32 (m, 1H), 5.34 - 5.29 (m, 1H), 4.27 (s, 4H), 3.92 - 3.87 (m, 2H), 3.83 - 3.74 (m, 2H), 2.74 (s, 3H), 2.66 (s, 3H), 2.29 - 2.21 (m, 2H), 1.60 (d,J = 7.1, 3H)。LCMS [M+1]⁺ : 415.2。 12-72

(R )-2-甲基-3-(1-((4-甲基-7-(5-甲基-8-氧雜-2,5-二氮雜螺[3.5]壬-2-基)吡啶并[3,4-d]嗒

-1-基)胺基)乙基)苯甲腈 甲酸鹽 ¹ H NMR (400 MHz, CD₃ OD) δ 9.06 (s, 1H), 8.49 (s, 1H), 7.72 (dd,J = 7.9, 1.3 Hz, 1H), 7.51 (dd,J = 7.7, 1.3 Hz, 1H), 7.27 (t,J = 7.8 Hz, 1H), 7.15 (s, 1H), 5.50 (q,J = 6.9 Hz, 1H), 4.38 (d,J = 10.0 Hz, 2H), 3.89 (dd,J = 10.0, 2.9 Hz, 2H), 3.82 - 3.73 (m, 4H), 2.71 (s, 3H), 2.69 (s, 3H), 2.65 - 2.58 (m, 2H), 2.50 (s, 3H), 1.63 (d,J = 7.0 Hz, 3H)。LCMS [M+1]⁺ : 444.2。 12-73

3-((R )-1-((7-((R )-六氫吡咯并[1,2-a]吡

-2(1H )-基)-4-甲基吡啶并[3,4-d ]嗒

-1-基)胺基)乙基)-2-甲基苯甲腈 ¹ H NMR (400 MHz, 甲醇-d ₄ ) δ 8.99 (d,J = 0.9 Hz, 1H), 7.70 (dd,J = 7.9, 1.4 Hz, 1H), 7.49 (dd,J = 7.7, 1.4 Hz, 1H), 7.34 (d,J = 1.0 Hz, 1H), 7.24 (t,J = 7.8 Hz, 1H), 5.57 (q,J = 6.9 Hz, 1H), 4.71 (d,J = 12.4 Hz, 1H), 4.62 (d,J = 13.4 Hz, 1H), 3.24 - 3.07 (m, 3H), 2.85 - 2.72 (m, 2H), 2.72 (s, 3H), 2.61 (s, 3H), 2.41 - 2.13 (m, 3H), 2.06 - 1.91 (m, 1H), 1.94 - 1.83.(m, 1H), 1.61 (d,J = 6.9 Hz, 3H), 1.61 - 1.48 (m, 1H)。LCMS [M+1]⁺ : 428.2。 12-74

N -((R )-1-(2-氯-3-氟苯基)乙基)-7-((S )-六氫吡

并[2,1-c ][1,4]

-8(1H )-基)-4-甲基吡啶并[3,4-d ]嗒

-1-胺 甲酸鹽 ¹ H NMR (400 MHz, CD₃ OD) δ = 9.13 (s, 1H), 8.45 (s, 1H), 7.47 (s, 1H), 7.30 - 7.23 (m, 1H), 7.26 - 7.16 (m, 1H), 7.13 - 7.04 (m, 1H), 5.62 (q,J = 7.0 Hz, 1H), 4.72 (d,J = 13.3 Hz, 1H), 4.54 - 4.47 (m, 1H), 3.92 - 3.80 (m, 2H), 3.79 - 3.68 (m, 1H), 3.37 (t,J = 10.6 Hz, 1H), 3.31 - 3.20 (m, 1H), 3.02 - 2.93 (m, 1H), 2.83 - 2.72 (m, 2H), 2.70 (s, 3H), 2.46 - 2.35 (m, 2H), 2.39 - 2.28 (m, 1H), 1.65 (d,J = 7.0 Hz, 3H)。LCMS [M+1]⁺ : 457.2。 12-75

N -((R )-1-(2,3-二氟苯基)乙基)-7-((S )-六氫吡

并[2,1-c ][1,4]

-8(1H )-基)-4-甲基吡啶并[3,4-d ]嗒

-1-胺 甲酸鹽 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.99 (s, 1H), 7.47 (d,J = 7.1 Hz, 1H), 7.41 (s, 1H), 7.30 - 7.15 (m, 2H), 7.14 - 7.04 (m, 1H), 5.67 - 5.59 (m, 1H), 4.44 (d,J = 12.5 Hz, 1H), 4.37 (d,J = 12.4 Hz, 1H), 3.86 - 3.76 (m, 2H), 3.63 - 3.52 (m, 1H), 3.29 - 3.19 (m, 1H), 3.14 - 3.02 (m, 1H), 2.92 (d,J = 11.5 Hz, 1H), 2.73 (d,J = 11.3 Hz, 1H), 2.64 - 2.57 (m, 1H), 2.56 (s, 3H), 2.36 - 2.18 (m, 3H), 1.60 (d,J = 7.0 Hz, 3H)。LCMS [M+1]⁺ : 441.1。 12-76

2-甲基-3-((R )-1-((4-甲基-7-((1R ,4R )-5-(2,2,2-三氟乙基)-2,5-二氮雜雙環[2.2.2]辛-2-基)吡啶并[3,4-d ]嗒

-1-基)胺基)乙基)苯甲腈 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.93 (s, 1H), 7.72 (d,J = 8.0 Hz, 1H), 7.61 (d,J = 7.5 Hz, 1H), 7.47 (d,J = 6.8 Hz, 1H), 7.31 (t,J = 7.8 Hz, 1H), 7.08 (s, 1H), 5.57 - 5.46 (m, 1H), 3.78 (d,J = 11.2 Hz, 1H), 3.56 - 3.44 (m, 1H), 3.24 - 3.07 (m, 4H), 2.65 (s, 3H), 2.52 (s, 3H), 2.13 - 1.97 (m, 1H), 1.93 - 1.78 (m, 2H), 1.76 - 1.67 (m, 2H), 1.54 (d,J = 6.9 Hz, 3H)。LCMS [M+1]⁺ : 496.0。 12-77

7-(6-氧雜-3-氮雜雙環[3.1.1]庚-3-基)-N -((R )-1-(2-氯-3-氟苯基)乙基)-4-甲基吡啶并[3,4-d ]嗒

-1-胺 甲酸鹽 ¹ H NMR (400 MHz, CD₃ OD) δ  = 9.17 (s, 1H), 8.51 (s, 1H), 7.35 (s, 1H), 7.33 - 7.27 (m, 1H), 7.27 - 7.17 (m, 1H), 7.14 - 7.05 (m, 1H), 5.68 (q,J = 6.9 Hz, 1H), 4.87 (s, 2H), 4.02 (d,J = 13.0 Hz, 2H), 3.88 (d,J = 12.8 Hz, 2H), 3.42 - 3.34 (m, 1H), 2.72 (s, 3H), 2.07 - 2.00 (m, 1H), 1.68 (d,J = 7.0 Hz, 3H)。LCMS [M+1]⁺ : 414.2。 12-78

(R )-2-甲基-3-(1-((4-甲基-7-(6-(2,2,2-三氟乙基)-2,6-二氮雜螺[3.4]辛-2-基)吡啶并[3,4-d ]嗒

-1-基)胺基)乙基)苯甲腈 甲酸鹽 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ  = 8.97 (s, 1H), 7.71 (d,J = 8.0 Hz, 1H), 7.61 (d,J = 7.7 Hz, 1H), 7.58 - 7.52 (m, 1H), 7.32 (t,J = 7.8 Hz, 1H), 7.08 (s, 1H), 5.48 (q,J = 6.9 Hz, 1H), 4.11 - 4.01 (m, 4H), 3.32 - 3.25 (m, 2H), 3.00 (s, 2H), 2.80 (t,J = 7.1 Hz, 2H), 2.64 (s, 3H), 2.55 (s, 3H), 2.13 (t,J = 7.0 Hz, 2H), 1.53 (d,J = 6.9 Hz, 3H)。LCMS [M+1]⁺ : 496.4。 12-79

N -((R )-1-(4-氟-2-甲基苯基)乙基)-7-((S )-六氫吡

并[2,1-c ][1,4]

-8(1H )-基)-4-甲基吡啶并[3,4-d ]嗒

-1-胺 ¹ H NMR (400 MHz, CD₃ OD) δ  = 9.25 (s, 1H), 7.59 (s, 1H), 7.43 (dd,J = 8.6, 5.8 Hz, 1H), 6.95 - 6.84 (m, 2H), 5.40 (q,J = 7.0 Hz, 1H), 3.98 - 3.69 (m, 3H), 3.51 - 3.37 (m, 4H), 3.22 - 2.86 (m, 3H), 2.81 (s, 3H), 2.68 - 2.53 (m, 3H), 2.50 (s, 3H), 1.65 (d,J = 6.9 Hz, 3H)。LCMS [M+1]⁺ : 437.3。 12-80

(R )-1-(1-((1-(2-氯-3-氟苯基)乙基)胺基)-4-甲基吡啶并[3,4-d ]嗒

-7-基)-3-甲基氮雜環丁烷-3-醇 甲酸鹽 ¹ H NMR (400 MHz, CD₃ OD) δ = 9.06 (d,J = 0.8 Hz, 1H), 8.48 (s, 1H), 7.29 - 7.16 (m, 2H), 7.15 - 7.10 (m, 1H), 7.13 - 7.04 (m, 1H), 5.63 (q,J = 6.9 Hz, 1H), 4.21 - 4.14 (m, 2H), 4.14 - 4.08 (m, 2H), 2.68 (s, 3H), 1.65 (d,J = 7.0 Hz, 3H), 1.60 (s, 3H)。LCMS [M+1]⁺ : 402.2。 12-81

(R )-1-(1-((1-(3-氟-2-甲基苯基)乙基)胺基)-4-甲基吡啶并[3,4-d ]嗒

-7-基)-3-甲基氮雜環丁烷-3-醇 ¹ H NMR (400 MHz, CD₃ OD) δ = 8.94 - 8.89 (m, 1H), 7.22 (d,J = 7.7 Hz, 1H), 7.13 - 7.00 (m, 2H), 6.86 (t,J = 8.9 Hz, 1H), 5.58 (q,J = 6.9 Hz, 1H), 4.13 - 4.07 (m, 2H), 4.07 - 4.01 (m, 2H), 2.62 (s, 3H), 2.37 (s, 3H), 1.62 - 1.56 (m, 6H)。LCMS [M+1]⁺ : 382.3。 12-82

(R )-7-(3-(二甲基胺基)-3-甲基氮雜環丁烷-1-基)-N -(1-(3-氟-2-甲基苯基)乙基)-4-甲基吡啶并[3,4-d ]嗒

-1-胺 二鹽酸鹽 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ  = 14.91 (s, 1H), 12.41 (s, 1H), 9.12 (s, 1H), 8.90 (s, 1H), 7.67 (s, 1H), 7.22 (d,J = 7.8 Hz, 1H), 7.08 - 6.98 (m, 1H), 6.86 (t,J = 9.0 Hz, 1H), 5.23 - 5.11 (m, 1H), 4.54 - 4.46 (m, 2H), 4.06 - 4.01 (m, 2H), 2.64 (s, 3H), 2.57 (s, 6H), 2.20 (s, 3H), 1.56 (s, 3H), 1.47 (d,J = 6.9 Hz, 3H)。LCMS [M+1]⁺ : 409.2。 12-83

(R )-N -(1-(2,3-二氟苯基)乙基)-7-(3-(二甲基胺基)-3-甲基氮雜環丁烷-1-基)-4-甲基吡啶并[3,4-d ]嗒

-1-胺 甲酸鹽 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ  = 8.97 (s, 1H), 8.14 (s, 1H), 7.45 (s, 1H), 7.30 - 7.16 (m, 2H), 7.13 - 7.06 (m, 2H), 5.63 - 5.59 (m, 1H), 3.91 (dd,J = 8.2, 4.3 Hz, 2H), 3.85 - 3.78 (m, 2H), 2.56 (s, 3H), 2.16 (s, 6H), 1.60 (d,J = 7.0 Hz, 3H), 1.33 (s, 3H)。LCMS [M+1]⁺ : 413.1。 12-84

7-(6-氧雜-3-氮雜雙環[3.1.1]庚-3-基)-N -((R )-1-(4-氟-2-甲基苯基)乙基)-4-甲基吡啶并[3,4-d ]嗒

-1-胺 ¹ H NMR (400 MHz, CD₃ OD) δ 9.19 (s, 1H), 7.44 (dd,J = 8.6, 5.9 Hz, 1H), 7.34 (s, 1H), 6.93 - 6.80 (m, 2H), 5.48 (q,J = 6.9 Hz, 1H), 4.85 (s, 2H), 4.02 (d,J = 13.0 Hz, 2H), 3.88 (d,J = 12.9 Hz, 2H), 3.41 - 3.33 (m, 1H), 2.76 (s, 3H), 2.49 (s, 3H), 2.02 (d,J = 9.1 Hz, 1H), 1.64 (d,J = 6.9 Hz, 3H)。LCMS [M+1]⁺ : 394.3。 12-85

(R )-N -(1-(2-氯-3-氟苯基)乙基)-7-(3-(二甲基胺基)-3-甲基氮雜環丁烷-1-基)-4-甲基吡啶并[3,4-d ]嗒

-1-胺 甲酸鹽 ¹ H NMR (400 MHz, CD₃ OD) δ = 9.03 (d,J = 0.8 Hz, 1H), 7.30 - 7.23 (m, 1H), 7.25 - 7.15 (m, 1H), 7.12 (s, 1H), 7.12 - 7.03 (m, 1H), 5.65 (q,J = 7.0 Hz, 1H), 4.09 (d,J = 8.9 Hz, 2H), 3.95 (d,J = 8.8 Hz, 2H), 2.66 (s, 3H), 2.30 (s, 6H), 1.65 (d,J = 6.9 Hz, 3H), 1.47 (s, 3H)。LCMS [M+1]⁺ : 429.2。 12-86

2-甲基-3-((R )-1-((4-甲基-7-((R )-八氫-2H -吡啶并[1,2-a ]吡

-2-基)吡啶并[3,4-d ]嗒

-1-基)胺基)乙基)苯甲腈 甲酸鹽 ¹ H NMR (400 MHz, CD₃ OD) δ = 9.09 (s, 1H), 7.72 (d,J = 8.0 Hz, 1H), 7.53 (d,J = 7.7 Hz, 1H), 7.41 (s, 1H), 7.28 (t,J = 7.8 Hz, 1H), 5.54 (q,J = 7.0 Hz, 1H), 4.70 (d,J = 13.2 Hz, 1H), 4.51 (d,J = 13.2 Hz, 1H), 3.28 - 3.16 (m, 1H), 3.04 - 2.96 (m, 2H), 2.84 (dd,J = 13.2, 10.7 Hz, 1H), 2.74 (s, 3H), 2.69 (s, 3H), 2.41 (td,J = 12.0, 3.3 Hz, 1H), 2.27 - 2.13 (m, 2H), 1.92 - 1.85 (m, 1H), 1.83 - 1.69 (m, 3H), 1.64 (d,J = 7.0 Hz, 3H), 1.50 - 1.33 (m, 2H)。LCMS [M+1]⁺ : 442.3。 12-87

(R )-2-甲基-3-(1-((4-甲基-7-(3-甲基-3-

啉基氮雜環丁烷-1-基)吡啶并[3,4-d ]嗒

-1-基)胺基)乙基)苯甲腈 甲酸鹽 ¹ H NMR (400 MHz, CD₃ OD) δ = 9.04 (d,J = 0.9 Hz, 1H), 8.51 (s, 1H), 7.72 (dd,J = 7.9, 1.4 Hz, 1H), 7.52 (dd,J = 7.7, 1.4 Hz, 1H), 7.28 (t,J = 7.8 Hz, 1H), 7.08 (s, 1H), 5.52 (q,J = 6.9 Hz, 1H), 4.12 - 4.04 (m, 2H), 3.95 - 3.87 (m, 2H), 3.78 - 3.71 (m, 4H), 2.72 (s, 3H), 2.68 (s, 3H), 2.61 - 2.49 (m, 4H), 1.63 (d,J = 7.0 Hz, 3H), 1.47 (s, 3H)。LCMS [M+1]⁺ : 458.3。 12-88

(R )-2-甲基-3-(1-((4-甲基-7-(5-甲基-2,5-二氮雜螺[3.4]辛-2-基)吡啶并[3,4-d ]嗒

-1-基)胺基)乙基)苯甲腈 ¹ H NMR (400 MHz, CD₃ OD) δ = 8.95 (d,J = 0.9 Hz, 1H), 7.72 (dd,J = 7.9, 1.4 Hz, 1H), 7.50 (dd,J = 7.7, 1.3 Hz, 1H), 7.26 (t,J = 7.8 Hz, 1H), 7.05 (d,J = 0.9 Hz, 1H), 5.58 (q,J = 6.9 Hz, 1H), 4.34 (dd,J = 9.2, 3.3 Hz, 2H), 3.99 (d,J = 9.2 Hz, 2H), 2.82 (t,J = 7.3 Hz, 2H), 2.73 (s, 3H), 2.62 (s, 3H), 2.51 (s, 3H), 2.26 - 2.18 (m, 2H), 1.94 - 1.82 (m, 2H), 1.62 (d,J = 6.9 Hz, 3H)。LCMS [M+1]⁺ : 428.2。 12-89

3-((R )-1-((7-((1R ,4R )-5-(2-羥乙基)-2,5-二氮雜雙環[2.2.2]辛-2-基)-4-甲基吡啶并[3,4-d ]嗒

-1-基)胺基)乙基)-2-甲基苯甲腈 ¹ H NMR (400 MHz, CD₃ OD) δ 9.19 (s, 1H), 7.76 (dd,J = 7.9, 1.4 Hz, 1H), 7.54 (dd,J = 7.8, 1.3 Hz, 1H), 7.35 (s, 1H), 7.29 (t,J = 7.8 Hz, 1H), 5.47 (q,J = 6.9 Hz, 1H), 5.15 (s, 1H), 4.14 (dt,J = 12.8, 2.7 Hz, 1H), 3.85 - 3.68 (m, 4H), 3.45 - 3.41 (m, 2H), 3.27 - 3.12 (m, 2H), 2.76 (s, 3H), 2.73 (s, 3H), 2.39 - 2.34 (m, 1H), 2.11 - 2.02 (m, 2H), 2.00 - 1.88 (m, 1H), 1.67 (d,J = 7.0 Hz, 3H)。LCMS [M+1]⁺ : 458.2。 12-90

(R )-3-(1-((7-(4-(2-甲氧基乙基)哌

-1-基)-4-甲基吡啶并[3,4-d ]嗒

-1-基)胺基)乙基)-2-甲基苯甲腈 ¹ H NMR (400 MHz, CD₃ OD) δ = 8.97 (d,J = 0.8 Hz, 1H), 7.72 (dd,J = 8.0, 1.4 Hz, 1H), 7.48 (dd,J = 7.7, 1.4 Hz, 1H), 7.30 (d,J = 0.9 Hz, 1H), 7.24 (t,J = 7.8 Hz, 1H), 5.57 (q,J = 6.9 Hz, 1H), 3.84 - 3.77 (m, 4H), 3.60 (t,J = 5.5 Hz, 2H), 3.38 (s, 3H), 2.71 (s, 3H), 2.69 - 2.64 (m, 6H), 2.61 (s, 3H), 1.61 (d,J = 7.0 Hz, 3H)。LCMS [M+1]⁺ : 446.2。 12-91

(R )-2-甲基-3-(1-((4-甲基-7-(6-甲基-2,6-二氮雜螺[3.3]庚-2-基)吡啶并[3,4-d ]嗒

-1-基)胺基)乙基)苯甲腈 甲酸鹽 ¹ H NMR (400 MHz, CD₃ OD) δ = 9.11 (s, 1H), 7.73 (d,J = 7.8 Hz, 1H), 7.54 (dd,J = 7.7, 1.3 Hz, 1H), 7.29 (t,J = 7.8 Hz, 1H), 7.20 (s, 1H), 5.47 (q,J = 6.8 Hz, 1H), 4.50 (s, 4H), 4.36 (s, 4H), 2.90 (s, 3H), 2.73 (s, 6H), 1.66 (d,J = 7.0 Hz, 3H)。LCMS [M+1]⁺ : 414.1。 12-92

(R )-N -(1-(2-氟-3-(三氟甲基)苯基)乙基)-4-甲基-7-(6-甲基-2,6-二氮雜螺[3.3]庚-2-基)吡啶并[3,4-d ]嗒

-1-胺 ¹ H NMR (400 MHz, CD₃ OD) δ 8.95 (s, 1H), 7.71 - 7.62 (m, 1H), 7.57 - 7.48 (m, 1H), 7.26 - 7.18 (m, 1H), 7.05 (s, 1H), 5.69 (q,J = 7.0 Hz, 1H), 4.29 (s, 4H), 3.54 (s, 4H), 2.61 (s, 3H), 2.39 (s, 3H), 1.69 (d,J = 7.0 Hz, 3H)。LCMS [M+1]⁺ : 461.6。 12-93

(R )-3-(1-((7-(4-(2-羥乙基)哌

-1-基)-4-甲基吡啶并[3,4-d ]嗒

-1-基)胺基)乙基)-2-甲基苯甲腈 ¹ H NMR (400 MHz, CD₃ OD) δ = 8.98 (s, 1H), 7.72 (dd,J = 7.9, 1.3 Hz, 1H), 7.49 (dd,J = 7.7, 1.3 Hz, 1H), 7.31 (s, 1H), 7.25 (t,J = 7.8 Hz, 1H), 5.58 (q,J = 6.9 Hz, 1H), 3.86 - 3.79 (m, 4H), 3.76 (t,J = 5.9 Hz, 2H), 2.72 (s, 3H), 2.71 - 2.60 (m, 9H), 1.61 (d,J = 7.0 Hz, 3H)。LCMS [M+1]⁺ : 432.2。 12-94

(R )-3-(1-((7-(4-(環丙烷羰基)哌

-1-基)-4-甲基吡啶并[3,4-d ]嗒

-1-基)胺基)乙基)-2-甲基苯甲腈 甲酸鹽 ¹ H NMR (400 MHz, CD₃ OD) δ = 9.12 (s, 1H), 7.74 (dd,J = 8.0, 1.4 Hz, 1H), 7.53 (dd,J = 7.7, 1.4 Hz, 1H), 7.44 (s, 1H), 7.28 (t,J = 7.8 Hz, 1H), 5.54 (q,J = 6.9 Hz, 1H), 4.01 (d,J = 15.7 Hz, 4H), 3.84 (d,J = 24.5 Hz, 4H), 2.73 (s, 3H), 2.70 (s, 3H), 2.11 - 2.00 (m, 1H), 1.65 (d,J = 6.9 Hz, 3H), 1.00 - 0.91 (m, 2H), 0.94 - 0.85 (m, 2H)。LCMS [M+1]⁺ : 456.2。 12-95

(R )-3-(1-((7-(4-乙醯基哌

-1-基)-4-甲基吡啶并[3,4-d ]嗒

-1-基)胺基)乙基)-2-甲基苯甲腈 甲酸鹽 ¹ H NMR (400 MHz, CD₃ OD) δ = 9.10 (d,J = 0.8 Hz, 1H), 7.71 (dd,J = 8.0, 1.4 Hz, 1H), 7.51 (dd,J = 7.6, 1.3 Hz, 1H), 7.42 (s, 1H), 7.26 (t,J = 7.8 Hz, 1H), 5.50 (q,J = 7.0 Hz, 1H), 4.01 - 3.94 (m, 2H), 3.90 - 3.81 (m, 2H), 3.81 - 3.69 (m, 4H), 2.71 (s, 3H), 2.68 (s, 3H), 2.18 (s, 3H), 1.63 (d,J = 6.9 Hz, 3H)。LCMS [M+1]⁺ : 430.1。 12-96

3-((R )-1-((7-((R )-3-(二甲基胺基)吡咯啶-1-基)-4-甲基吡啶并[3,4-d ]嗒

-1-基)胺基)乙基)-2-甲基苯甲腈 ¹ H NMR (400 MHz, CD₃ OD) δ =  8.96 (d,J = 0.8 Hz, 1H), 7.73 (dd,J = 8.0, 1.3 Hz, 1H), 7.50 (dd,J = 7.5, 1.3 Hz, 1H), 7.25 (t,J = 7.8 Hz, 1H), 7.03 (s, 1H), 5.59 (q,J = 6.9 Hz, 1H), 3.94 - 3.84 (m, 2H), 3.63 - 3.51 (m, 1H), 3.41 - 3.34 (m, 1H), 3.06 - 2.96 (m, 1H), 2.73 (s, 3H), 2.62 (s, 3H), 2.39 (s, 7H), 2.07 - 1.91 (m, 1H), 1.63 (d,J = 6.9 Hz, 3H)。LCMS [M+1]⁺ : 416.2。 12-97

7-((S )-3-(二甲基胺基)吡咯啶-1-基)-N -((R )-1-(2-氟-3-(三氟甲基)苯基)乙基)-4-甲基吡啶并[3,4-d ]嗒

-1-胺 甲酸鹽 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.97 (s, 1H), 7.70 (t,J = 7.2 Hz, 1H), 7.61 (t,J = 7.2 Hz, 1H), 7.47 (d,J = 6.6 Hz, 1H), 7.30 (t,J = 7.8 Hz, 1H), 7.07 (s, 1H), 5.68 - 5.61 (m, 1H), 3.87 - 3.79 (m, 1H), 3.79 - 3.72 (m, 1H), 3.56 - 3.44 (m, 1H), 3.34 - 3.25 (m, 1H), 2.95 - 2.86 (m, 1H), 2.54 (s, 3H), 2.26 (s, 7H), 1.98 - 1.83 (m, 1H), 1.61 (d,J = 7.0 Hz, 3H)。LCMS [M+1]⁺ : 463.2。 12-98

7-(6-氧雜-3-氮雜雙環[3.1.1]庚-3-基)-N -((R )-1-(2,3-二氟苯基)乙基)-4-甲基吡啶并[3,4-d ]嗒

-1-胺 ¹ H NMR (400 MHz, CD₃ OD) δ = 9.08 (s, 1H), 7.24 (s, 1H), 7.20 (t,J = 7.0 Hz, 1H), 7.12 - 6.99 (m, 2H), 5.70 (q,J = 7.0 Hz, 1H), 3.99 (d,J = 12.7 Hz, 2H), 3.84 (d,J = 12.5 Hz, 2H), 3.41 - 3.34 (m, 2H), 2.66 (s, 3H), 2.08 - 2.01 (m, 1H), 1.70 (d,J = 7.0 Hz, 3H)。LCMS [M+1]⁺ : 398.0。 12-99

7-((1R ,4R )-2-氧雜-5-氮雜雙環[2.2.1]庚-5-基)-N -((R )-1-(3-(二氟甲基)-2-氟苯基)乙基)-4-甲基吡啶并[3,4-d ]嗒

-1-胺 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.97 (s, 1H), 7.56 (t,J = 7.3 Hz, 1H), 7.43 (dt,J = 28.4, 8.1 Hz, 2H), 7.27 - 7.09 (m, 3H), 5.70 - 5.58 (m, 1H), 5.08 (s, 1H), 4.78 (s, 1H), 3.92 - 3.85 (m, 1H), 3.74 - 3.68 (m, 1H), 3.66 - 3.59 (m, 1H), 3.44 - 3.36 (m, 1H), 3.31 - 3.28 (m, 1H), 2.54 (s, 3H), 2.03 - 1.93 (m, 2H), 1.60 (d,J = 7.0 Hz, 3H)。LCMS [M+1]⁺ : 430.1。 12-100

N -((R )-1-(3-(二氟甲基)-2-氟苯基)乙基)-7-((S )-六氫吡

并[2,1-c ][1,4]

-8(1H )-基)-4-甲基吡啶并[3,4-d]嗒

-1-胺 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.99 (s, 1H), 7.56 (t,J = 7.5 Hz, 2H), 7.50 - 7.08 (m, 4H), 5.70 - 5.59 (m, 1H), 4.49 - 4.34 (m, 2H), 3.86 - 3.76 (m, 2H), 3.63 - 3.55 (m, 1H), 3.27 - 3.22 (m, 1H), 3.11 - 3.06 (m, 1H), 2.96 - 2.89 (m, 1H), 2.77 - 2.69 (m, 1H), 2.64 - 2.57 (m, 1H), 2.55 (s, 3H), 2.35 - 2.17 (m, 3H), 1.60 (d,J = 7.0 Hz, 3H)。LCMS [M+1]⁺ : 473.3。 12-101

(R )-1-(1-((1-(3-(二氟甲基)-2-氟苯基)乙基)胺基)-4-甲基吡啶并[3,4-d ]嗒

-7-基)-3-甲基氮雜環丁烷-3-醇 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.96 (s, 1H), 7.57 (t,J = 7.5 Hz, 1H), 7.51 - 7.41 (m, 2H), 7.28 - 7.20 (m, 1H), 7.13 - 7.07 (m, 1H), 5.73 (s, 1H), 5.70 - 5.59 (m, 1H), 4.06 - 3.93 (m, 4H), 2.55 (s, 3H), 1.60 (d,J = 7.0 Hz, 3H), 1.50 (s, 3H)。LCMS [M+1]⁺ : 418.0。 12-102

(R )-N -(1-(3-(二氟甲基)-2-氟苯基)乙基)-7-(4-乙基哌

-1-基)-4-甲基吡啶并[3,4-d ]嗒

-1-胺 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.00 (s, 1H), 7.60 - 7.10 (m, 5H), 5.70 - 5.60 (m, 1H), 3.74 (t,J = 5.1 Hz, 4H), 2.57 - 2.53 (m, 7H), 2.42 (q,J = 7.2 Hz, 2H), 1.61 (d,J = 7.0 Hz, 3H), 1.08 (t,J = 7.1 Hz, 3H)。LCMS [M+1]⁺ : 445.7。 12-103

5-氟-3-((R )-1-((7-((S )-六氫吡

并[2,1-c ][1,4]

-8(1H )-基)-4-甲基吡啶并[3,4-d ]嗒

-1-基)胺基)乙基)-2-甲基苯甲腈 甲酸鹽 ¹ H NMR (400 MHz, CD₃ OD) δ = 9.18 (s, 1H), 8.33 (s, 1H), 7.50 - 7.43 (m, 2H), 7.35 (dd,J = 7.9, 2.8 Hz, 1H), 5.46 - 5.36 (m, 1H), 4.74 (d,J = 13.5 Hz, 1H), 4.54 (d,J = 13.0 Hz, 1H), 3.93 - 3.82 (m, 2H), 3.79 - 3.68 (m, 1H), 3.43 - 3.33 (m, 1H), 3.31 - 3.23 (m, 1H), 3.03 - 2.95 (m, 1H), 2.87 - 2.77 (m, 2H), 2.75 (s, 3H), 2.70 (s, 3H), 2.47 - 2.29 (m, 3H), 1.63 (d,J = 7.0 Hz, 3H)。LCMS [M+1]⁺ : 462.2。 12-104

(R )-3-(1-((7-(4-(二甲基胺基)-4-甲基哌啶-1-基)-4-甲基吡啶并[3,4-d ]嗒

-1-基)胺基)乙基)-5-氟-2-甲基苯甲腈 ¹ H NMR (400 MHz, CD₃ OD) δ = 9.00 (d,J = 0.8 Hz, 1H), 7.47 (dd,J = 9.9, 2.8 Hz, 1H), 7.34 - 7.27 (m, 2H), 5.59 - 5.49 (m, 1H), 4.28 - 4.20 (m, 2H), 3.50 - 3.39 (m, 2H), 2.70 (s, 3H), 2.63 (s, 3H), 2.29 (s, 6H), 1.79 - 1.75 (m, 4H), 1.61 (d,J = 7.0 Hz, 3H), 1.13 (s, 3H)。LCMS [M+1]⁺ : 462.4。 12-105

3-((R )-1-((7-((1R ,4R )-2-氧雜-5-氮雜雙環[2.2.1]庚-5-基)-4-甲基吡啶并[3,4-d ]嗒

-1-基)胺基)乙基)-5-氟-2-甲基苯甲腈 ¹ H NMR (400 MHz, CD₃ OD) δ 8.98 (s, 1H), 7.46 (dd,J = 10.0, 2.8 Hz, 1H), 7.30 (dd,J = 7.9, 2.8 Hz, 1H), 7.07 (s, 1H), 5.58 - 5.48 (m, 1H), 5.17 (s, 1H), 4.81 (s, 1H), 4.00 - 3.93 (m, 1H), 3.87 (d,J = 7.4 Hz, 1H), 3.72 - 3.64 (m, 1H), 3.51 (d,J = 10.3 Hz, 1H), 2.70 (s, 3H), 2.64 (s, 3H), 2.10 - 2.05 (m, 2H), 1.61 (d,J = 7.0 Hz, 3H)。LCMS [M+1]⁺ : 419.3。 12-106

3-((1R )-1-((7-(6-氧雜-3-氮雜雙環[3.1.1]庚-3-基)-4-甲基吡啶并[3,4-d ]嗒

-1-基)胺基)乙基)-5-氟-2-甲基苯甲腈 甲酸鹽 ¹ H NMR (400 MHz, CD₃ OD) δ = 9.17 (s, 1H), 7.50 (dd,J = 9.9, 2.8 Hz, 1H), 7.32 (dd,J = 7.9, 2.8 Hz, 1H), 7.30 (s, 1H), 5.53 - 5.43 (m, 1H), 4.88 - 4.82 (m, 2H), 4.03 - 3.95 (m, 2H), 3.90 - 3.82 (m, 2H), 3.41 - 3.32 (m, 1H), 2.74 (s, 3H), 2.69 (s, 3H), 2.02 (d,J = 9.1 Hz, 1H), 1.64 (d,J = 7.0 Hz, 3H)。LCMS [M+1]⁺ : 419.2。 12-107

(R )-5-氟-3-(1-((7-(3-羥基-3-甲基氮雜環丁烷-1-基)-4-甲基吡啶并[3,4-d ]嗒

-1-基)胺基)乙基)-2-甲基苯甲腈 ¹ H NMR (400 MHz, CD₃ OD) δ = 9.02 (s, 1H), 7.47 (dd,J = 9.8, 2.8 Hz, 1H), 7.33 (dd,J = 7.9, 2.9 Hz, 1H), 7.06 (s, 1H), 5.47 (q,J = 7.0 Hz, 1H), 4.19 - 4.06 (m, 4H), 2.69 (s, 3H), 2.68 (s, 3H), 1.63 (s, 3H), 1.61 (d,J = 1.7 Hz, 3H)。LCMS [M+1]⁺ : 407.2。 12-108

(R )-3-(1-((7-(3-(二甲基胺基)-3-甲基氮雜環丁烷-1-基)-4-甲基吡啶并[3,4-d ]嗒

-1-基)胺基)乙基)-5-氟-2-甲基苯甲腈 ¹ H NMR (400 MHz, CD₃ OD) δ 8.95 (s, 1H), 7.47 (dd,J = 9.9, 2.8 Hz, 1H), 7.29 (dd,J = 7.9, 2.8 Hz, 1H), 7.02 (s, 1H), 5.58 - 5.48 (m, 1H), 4.06 - 3.98 (m, 2H), 3.93 - 3.84 (m, 2H), 2.68 (s, 3H), 2.64 (s, 3H), 2.27 (s, 6H), 1.60 (d,J = 7.0 Hz, 3H), 1.45 (s, 3H)。LCMS [M+1]⁺ : 434.2。 12-109

7-((1R ,4R )-2-氧雜-5-氮雜雙環[2.2.1]庚-5-基)-N -((R )-1-(5-氟-2-甲基-3-(三氟甲基)苯基)乙基)-4-甲基吡啶并[3,4-d ]嗒

-1-胺 ¹ H NMR (400 MHz, CD₃ OD) δ = 9.00 (s, 1H), 7.43 (dd,J = 9.9, 2.8 Hz, 1H), 7.25 (dd,J = 8.8, 2.8 Hz, 1H), 7.10 (s, 1H), 5.69 - 5.59 (m, 1H), 5.18 (s, 1H), 4.82 (s, 1H), 4.01 - 3.94 (m, 1H), 3.91 - 3.85 (m, 1H), 3.74 - 3.66 (m, 1H), 3.56 - 3.49 (m, 1H), 2.64 (s, 3H), 2.60 (s, 3H), 2.11 - 2.06 (m, 2H), 1.62 (d,J = 6.9 Hz, 3H)。LCMS [M+1]⁺ : 462.0。 12-110

(R )-7-(3-(二甲基胺基)-3-甲基氮雜環丁烷-1-基)-N -(1-(5-氟-2-甲基-3-(三氟甲基)苯基)乙基)-4-甲基吡啶并[3,4-d ]嗒

-1-胺 ¹ H NMR (400 MHz, CD₃ OD) δ = 8.98 (s, 1H), 7.43 (dd,J = 9.8, 2.8 Hz, 1H), 7.26 (dd,J = 8.9, 2.8 Hz, 1H), 7.06 (s, 1H), 5.68 - 5.60 (m, 1H), 4.10 - 4.02 (m, 2H), 3.97 - 3.89 (m, 2H), 2.64 (s, 3H), 2.59 (s, 3H), 2.29 (s, 6H), 1.62 (d,J = 7.0 Hz, 3H), 1.47 (s, 3H)。LCMS [M+1]⁺ : 477.0。 12-111

(R )-1-(1-((1-(5-氟-2-甲基-3-(三氟甲基)苯基)乙基)胺基)-4-甲基吡啶并[3,4-d ]嗒

-7-基)-3-甲基氮雜環丁烷-3-醇 ¹ H NMR (400 MHz, CD₃ OD) δ = 8.96 (s, 1H), 7.43 (dd,J = 9.9, 2.8 Hz, 1H), 7.26 (dd,J = 8.9, 2.8 Hz, 1H), 7.04 (s, 1H), 5.64 (q,J = 6.9 Hz, 1H), 4.14 (dd,J = 8.8, 3.4 Hz, 2H), 4.08 (dd,J = 8.8, 3.7 Hz, 2H), 2.63 (s, 3H), 2.60 (s, 3H), 1.65 - 1.59 (m, 6H)。LCMS [M+1]⁺ : 450.4。 12-112

N -((R )-1-(5-氟-2-甲基-3-(三氟甲基)苯基)乙基)-7-((S )-六氫吡

并[2,1-c ][1,4]

-8(1H )-基)-4-甲基吡啶并[3,4-d ]嗒

-1-胺 ¹ H NMR (400 MHz, CD₃ OD) δ = 9.04 (s, 1H), 7.46 - 7.39 (m, 1H), 7.36 (s, 1H), 7.29 - 7.22 (m, 1H), 5.69 - 5.61 (m, 1H), 4.68 - 4.57 (m, 1H), 4.48 - 4.40 (m, 1H), 3.94 - 3.85 (m, 2H), 3.81 - 3.70 (m, 1H), 3.45 - 3.35 (m, 1H), 3.25 - 3.15 (m, 1H), 3.02 - 2.94 (m, 1H), 2.85 - 2.78 (m, 1H), 2.77 - 2.67 (m, 1H), 2.65 (s, 3H), 2.60 (s, 3H), 2.48 - 2.32 (m, 3H), 1.62 (d,J = 6.9 Hz, 3H)。LCMS [M+1]⁺ : 505.5。 12-113

7-(6-氧雜-3-氮雜雙環[3.1.1]庚-3-基)-N -((R )-1-(5-氟-2-甲基-3-(三氟甲基)苯基)乙基)-4-甲基吡啶并[3,4-d ]嗒

-1-胺 ¹ H NMR (400 MHz, CD₃ OD) δ = 9.08 (s, 1H), 7.45 (d,J = 9.9 Hz, H), 7.27 - 7.17 (m, H), 5.70 - 5.63 (m, 1H), 4.03 - 3.96 (m, 3H), 3.88 - 3.80 (m, 2H), 3.39 - 3.34 (m, 2H), 2.67 (s, 2H), 2.61 (s, 3H), 2.05 (d,J = 8.9 Hz, 1H), 1.64 (d,J = 6.9 Hz, 2H)。LCMS [M+1]⁺ : 462.0。 12-114

3-((R )-1-((7-((1R ,4R )-2-氧雜-5-氮雜雙環[2.2.1]庚-5-基)-4-甲基吡啶并[3,4-d ]嗒

-1-基)胺基)乙基)-2,5-二氟苯甲腈 甲酸鹽 ¹ H NMR (400 MHz, CD₃ OD) δ = 9.07 (s, 1H), 8.52 (s, 1H), 7.63 - 7.55 (m, 1H), 7.41 - 7.32 (m, 1H), 7.15 (s, 1H), 5.60 - 5.51 (m, 1H), 5.25 - 5.20 (m, 1H), 4.62 - 4.58 (m, 1H), 4.02 - 3.95 (m, 1H), 3.92 - 3.85 (m, 1H), 3.75 - 3.68 (m, 1H), 3.61 - 3.52 (m, 1H), 2.68 (s, 3H), 2.10 (s, 2H), 1.70 (d,J = 7.0 Hz, 3H)。LCMS [M+1]⁺ : 423.2。 12-115

(R )-N -(1-(3-(二氟甲基)-2-氟苯基)乙基)-7-(3-(二甲基胺基)-3-甲基氮雜環丁烷-1-基)-4-甲基吡啶并[3,4-d ]嗒

-1-胺 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.96 (s, 1H), 7.57 (t,J = 7.5 Hz, 1H), 7.51 - 7.36 (m, 2H), 7.28 - 7.20 (m, 2H), 7.11 (s, 1H), 5.70 - 5.58 (m, 1H), 3.91 (dd,J = 8.2, 4.8 Hz, 2H), 3.81 (dd,J = 8.2, 2.1 Hz, 2H), 2.55 (s, 3H), 2.16 (s, 6H), 1.60 (d,J = 7.0 Hz, 3H), 1.33 (s, 3H)。LCMS [M+1]⁺ : 445.1。 12-116

(R )-N -(1-(3-(二氟甲基)-2-氟苯基)乙基)-4-甲基-7-(6-甲基-2,6-二氮雜螺[3.3]庚-2-基)吡啶并[3,4-d ]嗒

-1-胺 ¹ H NMR (400 MHz, CD₃ OD) δ = 8.94 (s, 1H), 7.55 (t,J = 7.5 Hz, 1H), 7.44 (t,J = 7.1 Hz, 1H), 7.21 - 6.85 (m, 3H), 5.68 (q,J = 7.0 Hz, 1H), 4.28 (s, 4H), 3.53 (s, 4H), 2.62 (s, 3H), 2.38 (s, 3H), 1.69 (d,J = 7.0 Hz, 3H)。LCMS [M+1]⁺ : 443.5。 12-117

(R )-N -(1-(3-(二氟甲基)-2-氟苯基)乙基)-4-甲基-7-(4-甲基哌

-1-基)吡啶并[3,4-d ]嗒

-1-胺 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.99 (s, 1H), 7.61 - 7.08 (m, 7H), 5.70 - 5.60 (m, 1H), 3.74 (t,J = 5.0 Hz, 4H), 2.56 (s, 3H), 2.49 - 2.43 (m, 4H), 2.27 (s, 3H), 1.61 (d,J = 7.0 Hz, 3H)。LCMS [M+1]⁺ : 431.2。 12-118

(R )-7-(4-乙基哌

-1-基)-N -(1-(5-氟-2-甲基-3-(三氟甲基)苯基)乙基)-4-甲基吡啶并[3,4-d ]嗒

-1-胺 ¹ H NMR (400 MHz, CD₃ OD) δ = 9.03 (s, 1H), 7.47 - 7.40 (m, 1H), 7.35 (s, 1H), 7.25 (dd,J = 8.8, 2.8 Hz, 1H), 5.64 (q,J = 6.9 Hz, 1H), 3.90 - 3.83 (m, 4H), 2.70 - 2.65 (m, 4H), 2.64 (s, 3H), 2.60 (s, 3H), 2.55 (q,J = 7.2 Hz, 2H), 1.62 (d,J = 6.9 Hz, 3H), 1.20 (t,J = 7.2 Hz, 3H)。LCMS [M+1]⁺ : 477.6。 12-119

(R )-N -(1-(5-氟-2-甲基-3-(三氟甲基)苯基)乙基)-4-甲基-7-(4-甲基哌

-1-基)吡啶并[3,4-d ]嗒

-1-胺 ¹ H NMR (400 MHz, CD₃ OD) δ = 9.04 (s, 1H), 7.43 (dd,J = 9.8, 2.7 Hz, 1H), 7.36 (s, 1H), 7.25 (dd,J = 8.9, 2.8 Hz, 1H), 5.64 (q,J = 7.1 Hz, 1H), 3.90 - 3.83 (m, 4H), 2.67 - 2.58 (m, 10H), 2.40 (s, 3H), 1.62 (d,J = 6.9 Hz, 3H)。LCMS [M+1]⁺ : 463.4。 12-120

2,5-二氟-3-((R )-1-((7-((S )-六氫吡

并[2,1-c ][1,4]

-8(1H )-基)-4-甲基吡啶并[3,4-d ]嗒

-1-基)胺基)乙基)苯甲腈 ¹ H NMR (400 MHz, CD₃ OD) δ = 9.20 (d,J = 0.8 Hz, 1H), 7.62 (dd,J = 9.3, 5.0 Hz, 1H), 7.50 (s, 1H), 7.41 (dd,J = 9.4, 5.7 Hz, 1H), 5.49 (q,J = 7.0 Hz, 1H), 4.77 - 4.72 (m, 2H), 4.57 (d,J = 13.4 Hz, 2H), 3.94 - 3.84 (m, 2H), 3.75 (td,J = 11.5, 2.4 Hz, 1H), 3.45 - 3.35 (m, 1H), 3.01 (d,J = 11.5 Hz, 1H), 2.88 - 2.78 (m, 2H), 2.76 (s, 3H), 2.47 - 2.38 (m, 1H), 2.42 - 2.31 (m, 1H), 1.71 (d,J = 7.1 Hz, 3H)。LCMS [M+1]⁺ : 466.3。 12-121

3-((1R )-1-((7-(6-氧雜-3-氮雜雙環[3.1.1]庚-3-基)-4-甲基吡啶并[3,4-d ]嗒

-1-基)胺基)乙基)-2,5-二氟苯甲腈 ¹ H NMR (400 MHz, CD₃ OD) δ 9.10 (s, 1H), 7.58 (dd,J = 9.2, 5.1 Hz, 1H), 7.37 (dd,J = 9.5, 5.7 Hz, 1H), 7.24 (s, 1H), 5.62 (q,J = 7.1 Hz, 1H), 4.89 (s, 1H), 4.00 (d,J = 12.8 Hz, 2H), 3.86 (d,J = 12.6 Hz, 2H), 3.42 - 3.34 (m, 2H), 2.68 (s, 3H), 2.06 (d,J = 9.0 Hz, 1H), 1.71 (d,J = 7.0 Hz, 3H)。LCMS [M+1]⁺ : 423.1。 12-122

(R )-3-(1-((7-(3-(二甲基胺基)-3-甲基氮雜環丁烷-1-基)-4-甲基吡啶并[3,4-d ]嗒

-1-基)胺基)乙基)-2,5-二氟苯甲腈 甲酸鹽 ¹ H NMR (400 MHz, CD₃ OD) δ = 9.09 (d,J = 0.8 Hz, 1H), 8.45 (s, 1H), 7.60 (dd,J = 9.3, 5.1 Hz, 1H), 7.38 (dd,J = 9.5, 5.7 Hz, 1H), 7.12 (s, 1H), 5.52 (q,J = 7.0 Hz, 1H), 4.16 - 4.09 (m, 2H), 4.02 - 3.95 (m, 2H), 2.71 (s, 3H), 2.34 (s, 6H), 1.70 (d,J = 7.0 Hz, 3H), 1.49 (s, 3H)。LCMS [M+1]⁺ : 438.2。 12-123

(R )-3-(1-((7-(4-(二甲基胺基)-4-甲基哌啶-1-基)-4-甲基吡啶并[3,4-d ]嗒

-1-基)胺基)乙基)-2,5-二氟苯甲腈 甲酸鹽 ¹ H NMR (400 MHz, CD₃ OD) δ = 9.07 (s, 1H), 8.51 (s, 1H), 7.59 (dd,J = 9.2, 5.1 Hz, 1H), 7.41 (s, 1H), 7.35 (dd,J = 9.5, 5.7 Hz, 1H), 5.55 (q,J = 7.3 Hz, 1H), 4.68 - 4.59 (m, 5H), 2.75 (s, 6H), 2.66 (s, 3H), 2.11 - 2.03 (m, 2H), 1.96 - 1.85 (m, 1H), 1.70 (d,J = 7.1 Hz, 3H), 1.48 (s, 3H)。LCMS [M+1]⁺ : 466.3。 12-124

(R )-7-(3-(二甲基胺基)-3-甲基氮雜環丁烷-1-基)-N -(1-(4-氟-2-甲基苯基)乙基)-4-甲基吡啶并[3,4-d ]嗒

-1-胺 ¹ H NMR (400 MHz, CD₃ OD) δ = 8.94 (s, 1H), 7.41 (dd,J = 8.6, 5.9 Hz, 1H), 7.02 (s, 1H), 6.90 - 6.77 (m, 2H), 5.56 (q,J = 6.9 Hz, 1H), 4.01 (d,J = 8.4 Hz, 2H), 3.88 (d,J = 8.4 Hz, 2H), 2.63 (s, 3H), 2.47 (s, 3H), 2.26 (s, 6H), 1.59 (d,J = 6.9 Hz, 3H), 1.44 (s, 3H)。LCMS [M+1]⁺ : 409.4。 12-125

N -((R )-1-(3-氟-2-甲基苯基)乙基)-7-((S )-六氫吡

并[2,1-c ][1,4]

-8(1H )-基)-4-甲基吡啶并[3,4-d ]嗒

-1-胺 二鹽酸鹽 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 15.02 (s, 1H), 12.35 (s, 1H), 9.48 (s, 1H), 9.30 (s, 1H), 8.48 (s, 1H), 7.47 (d,J = 7.8 Hz, 1H), 7.22 - 7.12 (m, 1H), 7.00 (t,J = 9.0 Hz, 1H), 5.39 - 5.31 (m, 1H), 5.15 - 5.03 (m, 2H), 4.27 - 4.20 (m, 1H), 4.03 - 3.95 (m, 2H), 3.79 - 3.71 (m, 3H), 3.35 - 3.06 (m, 2H), 3.59 - 3.55 (m, 2H), 2.80 (s, 3H), 2.37 (s, 3H), 1.66 (d,J = 7.0 Hz, 3H)。LCMS [M+1]⁺ : 473.3。 12-126

7-(6-氧雜-3-氮雜雙環[3.1.1]庚-3-基)-N -((R )-1-(3-氟-2-甲基苯基)乙基)-4-甲基吡啶并[3,4-d ]嗒

-1-胺 ¹ H NMR (400 MHz, CD₃ OD) δ = 9.04 (s, 1H), 7.25 (d,J = 7.8 Hz, 1H), 7.20 (s, 1H), 7.13 - 7.03 (m, 1H), 6.91 - 6.82 (m, 1H), 5.62 (q,J = 6.9 Hz, 1H), 4.87 - 4.81 (m, 2H), 3.99 - 3.91 (m, 2H), 3.85 - 3.76 (m, 2H), 3.38 - 3.32 (m, 1H), 2.65 (s, 3H), 2.40 - 2.35 (m, 3H), 2.02 (d, 1H), 1.61 (d,J = 7.0 Hz, 3H)。LCMS [M+1]⁺ : 394.3。 12-127

3-((R )-1-((7-((1R ,4R )-2-氧雜-5-氮雜雙環[2.2.1]庚-5-基)-4-甲基吡啶并[3,4-d ]嗒

-1-基)胺基)乙基)-2-(三氟甲基)苯甲腈 ¹ H NMR (400 MHz, CD₃ OD) δ = 8.97 (s, 1H), 8.04 (d,J = 8.0 Hz, 1H), 7.79 (d,J =7.6 Hz, 1H), 7.70 - 7.59 (m, 1H), 7.10 (s, 1H), 5.72 (q,J = 6.4 Hz, 1H), 5.16 (br s, 1H), 4.81 (s, 1H), 3.96 (dd,J =1.2, 7.2 Hz, 1H), 3.87 (d,J = 7.2 Hz, 1H), 3.69 (dd,J = 1.2, 10.0 Hz, 1H), 3.52 (br d,J = 10.4 Hz, 1H), 2.59 (s, 3H), 2.07 (s, 2H), 1.67 (d,J   = 6.8 Hz, 3H)。LCMS [M+1]⁺ : 455.3。 12-128

N-((R)-1-(4-胺基-6-(二氟甲基)吡啶-2-基)乙基)-7-((S)-六氫吡

并[2,1-c][1,4]

-8(1H)-基)-4-甲基吡啶并[3,4-d]嗒

-1-胺 ¹ H NMR (400 MHz, CD₃ OD) δ = 8.99 (s, 1H), 7.28 (s, 1H), 6.67 (q,J = 2.2 Hz, 2H), 6.49 (t,J = 55.6 Hz, 1H), 5.28 (q,J = 6.9 Hz, 1H), 4.56 (d,J = 13.1 Hz, 1H), 4.41 (d,J = 12.7 Hz, 1H), 3.91 - 3.81 (m, 2H), 3.72 (td,J = 11.5, 2.3 Hz, 1H), 3.36 (t,J = 10.7 Hz, 1H), 3.15 (td,J = 12.6, 3.1 Hz, 1H), 2.94 (d,J = 11.5 Hz, 1H), 2.78 (d,J = 11.6 Hz, 1H), 2.71 - 2.64 (m, 1H), 2.63 (s, 3H), 2.46 - 2.29 (m, 3H), 1.62 (d,J = 7.0 Hz, 3H)。LCMS [M+1]⁺ : 471.5。 12-129

N -((R )-1-(4-胺基-6-(二氟甲基)吡啶-2-基)乙基)-7-(6-氧雜-3-氮雜雙環[3.1.1]庚-3-基)-4-甲基吡啶并[3,4-d ]嗒

-1-胺 ¹ H NMR (400 MHz, CD₃ OD) δ = 9.06 (s, 1H), 7.15 (s, 1H), 6.73 - 6.68 (m, 2H), 6.52 (t,J = 55.7 Hz, 1H), 5.33 (q,J = 6.9 Hz, 1H), 4.85 (s, 2H), 3.96 (t,J = 11.6 Hz, 2H), 3.82 (dd,J = 12.7, 5.2 Hz, 2H), 3.40 - 3.33 (m, 1H), 2.67 (s, 3H), 2.05 (d,J = 9.0 Hz, 1H), 1.65 (d,J = 7.0 Hz, 3H)。LCMS [M+1]⁺ : 428.4。 12-130

(R )-1-(1-((1-(4-胺基-6-(二氟甲基)吡啶-2-基)乙基)胺基)-4-甲基吡啶并[3,4-d]嗒

-7-基)-3-甲基氮雜環丁烷-3-醇 ¹ H NMR (400 MHz, CD₃ OD) δ = 8.92 (s, 1H), 6.93 (s, 1H), 6.70 (s, 2H), 6.52 (t,J = 55.6 Hz, 1H), 5.29 (q,J = 6.9 Hz, 1H), 4.12 - 4.02 (m, 4H), 2.64 (s, 3H), 1.64 (d,J = 7.0 Hz, 3H), 1.60 (s, 3H)。LCMS [M+1]⁺ : 416.4。 12-131

N -((R )-1-(2-氟-3-甲基苯基)乙基)-7-((S )-六氫吡

并[2,1-c ][1,4]

-8(1H )-基)-4-甲基吡啶并[3,4-d ]嗒

-1-胺 ¹ H NMR (400 MHz, DMSO-d ₆ )δ = 8.97 (s, 1H), 8.31 (s, 1H), 7.41 (s, 1H), 7.36 (d, J = 7.2 Hz, 1H), 7.18 (t, J = 7.2 Hz, 1H), 7.09 - 7.04 (m, 1H), 6.95 (t, J = 7.6 Hz, 1H), 5.66 - 5.62 (m, 1H), 4.44 - 4.36 (m, 2H), 3.89 - 3.75 (m, 2H), 3.58 - 3.54 (m, 1H), 3.21 - 3.20 (m, 1H), 3.11 - 3.05 (m, 1H), 2.91 (d, J = 11.2 Hz, 1H), 2.72 (d, J = 11.6 Hz, 1H), 2.57- 2.56 (m, 1H), 2.55 (s, 3H), 2.30 - 2.26 (m, 1H), 2.24 (s, 3H), 2.22 - 2.15 (m, 2H), 1.56 (d, J = 7.2 Hz, 3H)。LCMS [M+1]⁺ : 437.1。 12-132

(R )-1-(1-((1-(2-氟-3-甲基苯基)乙基)胺基)-4-甲基吡啶并[3,4-d ]嗒

-7-基)-3-甲基氮雜環丁烷-3-醇 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.95 (s, 1H), 7.33 (d,J = 7.4 Hz, 1H), 7.18 (t,J = 7.2 Hz, 1H), 7.13 - 7.06 (m, 2H), 6.96 (t,J = 7.6 Hz, 1H), 5.71 (s, 1H), 5.64 (q,J = 7.0 Hz, 1H), 4.05 - 3.92 (m, 4H), 2.54 (s, 3H), 2.25 (s, 3H), 1.56 (d,J = 7.0 Hz, 3H), 1.49 (s, 3H)。LCMS [M+1]⁺ : 382.3。 12-133

(R )-7-(3-(二甲基胺基)-3-甲基氮雜環丁烷-1-基)-N -(1-(2-氟-3-甲基苯基)乙基)-4-甲基吡啶并[3,4-d ]嗒

-1-胺 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.94 (s, 1H), 8.28 (s, 0H), 7.32 (d,J = 7.3 Hz, 1H), 7.19 (t,J = 7.6 Hz, 1H), 7.10 (d,J = 4.2 Hz, 2H), 6.96 (t,J = 7.5 Hz, 1H), 5.62 (q,J = 6.9 Hz, 1H), 3.89 (dd,J = 8.2, 5.2 Hz, 2H), 3.79 (dd,J = 8.1, 3.2 Hz, 2H), 2.54 (s, 3H), 2.24 (s, 3H), 2.15 (s, 6H), 1.56 (d,J = 7.0 Hz, 3H), 1.32 (s, 3H)。LCMS [M+1]⁺ : 409.4。 12-134

7-(6-氧雜-3-氮雜雙環[3.1.1]庚-3-基)-N -((R )-1-(2-氟-3-甲基苯基)乙基)-4-甲基吡啶并[3,4-d ]嗒

-1-胺 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.04 (s, 1H), 7.45 (d,J = 7.4 Hz, 1H), 7.28 (s, 1H), 7.21 (t,J = 7.3 Hz, 1H), 7.09 (t,J = 7.2 Hz, 1H), 6.96 (t,J = 7.6 Hz, 1H), 5.67 (t,J = 7.1 Hz, 1H), 4.81 (d,J = 6.4 Hz, 2H), 3.95 - 3.85 (m, 2H), 3.77 - 3.67 (m, 2H), 2.57 (s, 3H), 2.25 (s, 3H), 1.95 (d,J = 8.8 Hz, 1H), 1.57 (d,J = 7.0 Hz, 3H)。LCMS [M+1]⁺ : 394.0。 實例13-1 4-甲基-N -((R )-1-(2-甲基-3-(三氟甲基)苯基)乙基)-7-(((S )-四氫呋喃-3-基)氧基)呔

-1-胺

Following the teaching of general reaction scheme III and the methods of preparing examples 12-1 and 12-2, the following compounds of formula (I), examples 12-3-12-134, as shown in Table 12, were prepared. Table 12 Example # structure Spectral data 12-3

( R )-4-methyl- N -(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-7-(2-oxa-6-azaspiro[3.3 ]Hept-6-yl)pyrido[3,4- d ]ta

-1-amine ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 8.94 (s, 1H), 7.72 (d, J = 7.6 Hz, 1H), 7.52 (d, J = 7.6 Hz, 2H), 7.34-7.28 (m , 1H), 7.10 (s, 1H), 5.67-5.57 (m, 1H), 4.78 (s, 4H), 4.29 (s, 4H), 2.56-2.52 (m, 6H), 1.54 (d, J = 6.8 Hz, 3H). LCMS [M+1] ⁺ : 444.1. 12-4

7-((2 R ,6 S )-2,6-dimethyl

(Alpinyl)-4-methyl- N -(( R )-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)pyrido[3,4-d]

-1-amine hydrochloride ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 14.73 (s, 1H), 9.23 (s, 1H), 9.19 (br s, 1H), 8.04 (s, 1H), 7.89 (d, J = 7.6 Hz, 1H), 7.55 (d, J = 7.6 Hz, 1H), 7.37-7.35 (m, 1H), 5.45-5.41 (m, 1H), 4.76-4.73 (m, 2H), 3.67-3.63 (m, 2H), 2.78-2.74 (m, 5H), 2.56 (s, 3H), 1.64 (d, J = 6.8 Hz, 3H), 1.23 (d, J = 4.8 Hz, 6H). LCMS [M+1] ⁺ : 460.1. 12-5

7-((2 R ,6 R )-2,6-dimethyl

(Alkolinyl)-4-methyl- N -(( R )-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)pyrido[3,4- d ]

-1-amine hydrochloride ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 14.66 (s, 1H), 9.23 (s, 1H), 9.00 (s, 1H), 7.90 (s, 1H), 7.83 (d, J = 7.6 Hz , 1H), 7.56 (d, J = 7.6 Hz, 1H), 7.36 (t, J = 8.0 Hz, 1H), 5.48-5.37 (m, 1H), 4.17-4.08 (m, 2H), 4.06-4.02 ( m, 2H), 3.74-3.69 (m, 2H), 2.73 (s, 3H), 2.56 (s, 3H), 1.63 (d, J = 6.8 Hz, 3H), 1.19 (d, J = 6.4 Hz, 6H ). LCMS [M+1] ⁺ : 460.1. 12-6

7-((2 S ,6 S )-2,6-dimethyl

(Alkolinyl)-4-methyl- N -(( R )-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)pyrido[3,4- d ]

-1-amine hydrochloride ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 14.65 (s, 1H), 9.25 (s, 1H), 8.92 (s, 1H), 7.91-7.78 (m, 2H), 7.57 (d, J = 8.0 Hz, 1H), 7.41-7.32 (m, 1H), 5.49-5.37 (m, 1H), 4.18-4.09 (m, 2H), 4.09-4.00 (m, 2H), 3.76-3.63 (m, 2H) , 2.73 (s, 3H), 2.56 (s, 3H), 1.63 (d, J = 7.2 Hz, 3H), 1.20 (d, J = 6.4 Hz, 6H). LCMS [M+1] ⁺ : 460.1. 12-7

( R )-4-methyl-1-(4-methyl-1-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyrido(3 ,4- d ]

-7-yl)piperidin-4-ol ¹ H NMR (400 MHz, CD ₃ OD) δ = 9.19 (s, 1H), 7.68 (d, J = 8.0 Hz, 1H), 7.58-7.51 (m, 2H), 7.32-7.26 (m, 1H), 5.49 (q, J = 6.8 Hz, 1H), 4.46 (br s, 2H), 3.58-3.51 (m, 2H), 2.75 (s, 3H), 2.61 (s, 3H), 1.81-1.68 (m, 4H ), 1.66 (d, J = 6.8 Hz, 3H), 1.31 (s, 3H). LCMS [M+1] ⁺ : 460.1. 12-8

7-((1 S ,4 S )-2-oxa-5-azabicyclo[2.2.1]hept-5-yl)-4-methyl- N -(( R )-1-(2- Methyl-3-(trifluoromethyl)phenyl)ethyl)pyrido[3,4- d ]

-1-amine ¹ H NMR (400 MHz, CD ₃ OD) δ = 8.96 (s, 1H), 7.68 (d, J = 8.0 Hz, 1H), 7.49 (d, J = 7.6 Hz, 1H), 7.29-7.19 (m, 1H), 7.10 (s, 1H), 5.74-5.61 (m, 1H), 5.15 (s, 1H), 4.80 (s, 1H), 3.95 (dd, J = 1.2, 7.6 Hz, 1H), 3.85 (d , J = 7.2 Hz, 1H), 3.66 (dd, J = 1.2, 10.4 Hz, 1H), 3.51 (d, J = 10.4 Hz, 1H), 2.61 (s, 6H), 2.14-1.99 (m, 2H) , 1.61 (d, J = 6.8 Hz, 3H). LCMS [M+1] ⁺ : 444.2. 12-9

7-((1 R ,4 R )-2-oxa-5-azabicyclo[2.2.1]hept-5-yl)-4-methyl- N -(( R )-1-(2- Methyl-3-(trifluoromethyl)phenyl)ethyl)pyrido[3,4- d ]

-1-amine ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 8.96 (s, 1H), 7.67 (d, J = 8.0 Hz, 1H), 7.48 (d, J = 7.6 Hz, 1H), 7.25-7.22 (m , 1H), 7.09 (s, 1H), 5.68-5.66 (m, 1H), 5.15 (s, 1H), 4.79 (s, 1H), 3.96-3.93 (m, 1H), 3.86-3.84 (m, 1H) ), 3.68-3.65 (m, 1H), 3.51 -3.49 (m, 1H), 2.61-2.60 (m, 6H), 2.06 (s, 2H), 1.61 (d, J = 7.2 Hz, 3H). LCMS [M+1] ⁺ : 444.1. 12-10

( R )-2-methyl-3-(1-((4-methyl-7-

Hydroxypyrido[3,4- d ]

-1-yl)amino)ethyl)benzonitrile ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 9.00 (s, 1H), 7.71 (d, J = 8.0 Hz, 1H), 7.61 (d, J = 1.2 7.6, Hz, 1H), 7.53 (d , J = 6.8 Hz, 1H), 7.40 (s, 1H), 7.32 (t, J = 7.6 Hz, 1H), 5.53 (m, 1H), 3.74-3.83 (m, 4H), 3.63-3.73 (m, 4H), 2.66 (s, 3H), 2.56 (s, 3H), 1.54 (d, J = 6.8 Hz, 3H). LCMS [M+1] ⁺ : 389.1 12-11

4-methyl- N -(( R )-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-7-((( S )-1-methylpyrrolidine- 3-yl)oxy)pyrido[3,4- d ]

-1-amine hydrochloride ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 9.44 (s, 1H), 8.25 (s, 1H), 7.75 (d, J = 7.6 Hz, 1H), 7.56 (d, J = 7.6 Hz, 1H ), 7.37-7.33 (m, 1H), 5.81-5.77 (m, 1H), 5.48-5.43 (m, 1H), 4.12-3.73 (m, 3H), 3.41-3.23 (m, 2H), 2.93-2.83 (m, 6H), 2.66-2.57 (m, 1H), 2.55 (s, 3H), 2.33-2.22 (m, 1H), 1.58 (d, J = 6.8 Hz, 3H). LCMS [M+1] ⁺ : 446.1. 12-12

( R )-4-methyl- N -(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-7-((1-methylazetidine-3 -Yl)oxy)pyrido[3,4-d]ta

-1-amine ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 9.07 (s, 1H), 7.84 (s, 1H), 7.73-7.71 (m, 1H), 7.51 (d, J = 7.6 Hz, 1H), 7.32 -7.30 (m, 1H), 5.64-5.59 (m, 1H), 5.27-5.24 (m, 1H), 3.79-3.75 (m, 2H), 3.06-3.01 (m, 2H), 2.61 (s, 3H) , 2.56 (s, 3H), 2.31 (s, 3H), 1.52 (d, J = 6.8 Hz, 3H). LCMS [M+1] ⁺ : 432.1. 12-13

( R )-4-(4-methyl-1-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyrido[3,4- d ] despair

-7-base) sulfur

Morpholino 1,1-dioxide ¹ H NMR (400 MHz, CD ₃ OD) δ = 9.31 (s, 1H), 7.81 (s, 1H), 7.71 (d, J = 8.0 Hz, 1H), 7.54 (d, J = 8.0 Hz, 1H) , 7.29 (t, J = 8.0 Hz, 1H), 5.53 (q, J = 6.8 Hz, 1H), 4.50 (br s, 4H), 3.30 (br s, 4H), 2.81 (s, 3H), 2.62 ( s, 3H), 1.68 (d, J = 6.8 Hz, 3H). LCMS [M+1] ⁺ : 480.2. 12-14

7-(( S )-hexahydropyridine

And [2,1- c ][1,4]

-8(1 H )-yl)-4-methyl- N -(( R )-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)pyrido[3,4 -d ] Da

-1-amine ¹ H NMR (400 MHz, CD ₃ OD) δ = 9.32 (s, 1H), 7.90 (br s, 1H), 7.78 (d, J = 7.6 Hz, 1H), 7.55 (d, J = 8.0 Hz, 1H ), 7.30 (t, J = 7.6 Hz, 1H), 5.55 (q, J = 6.8 Hz, 1H), 5.25-5.01 (m, 2H), 4.29-4.09 (m, 2H), 4.08-3.98 (m, 1H), 3.93-3.34 (m, 8H), 2.83 (s, 3H), 2.64 (s, 3H), 1.72 (d, J = 6.8 Hz, 3H). LCMS [M+1] ⁺ : 487.2. 12-15

( R )-7-(4-(dimethylamino)piperidin-1-yl)-4-methyl- N -(1-(2-methyl-3-(trifluoromethyl)phenyl )Ethyl)pyrido[3,4- d ]

-1-amine ¹ H NMR (400 MHz, CD ₃ OD) δ = 8.94 (s, 1H), 7.68 (d, J = 8.0 Hz, 1H), 7.48 (d, J = 7.8 Hz, 1H), 7.32 (s, 1H) , 7.23 (t, J = 7.6 Hz, 1H), 5.67 (q, J = 6.8 Hz, 1H), 4.77-4.65 (m, 2H), 3.05-2.94 (m, 2H), 2.61-2.58 (m, 6H ), 2.57-2.48 (m, 1H), 2.03-1.97 (m, 2H), 1.60 (d, J = 6.8 Hz, 3H), 1.55-1.43 (m, 2H). LCMS [M+1] ⁺ : 473.3. 12-16

( R )-6-methyl-2-(4-methyl-1-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyrido(3 ,4- d ]

-7-yl)-2,6-diazaspiro[3.4]octan-5-one ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 9.15 (s, 1H), 7.68 (d, J = 8.0 Hz, 1H), 7.54 (d, J = 7.6 Hz, 1H), 7.32 (t, J = 8.0 Hz, 1H), 7.28 (s, 1H), 5.35 (q, J = 6.8 Hz, 1H), 4.30 (d, J = 8.4 Hz, 2H), 4.19 (d, J = 2.8, 9.2 Hz, 2H ), 3.34 (t, J = 6.8 Hz, 2H), 2.78 (s, 3H), 2.69 (s, 3H), 2.52 (s, 3H), 2.41 (t, J = 6.8 Hz, 2H), 1.55 (d , J = 6.8 Hz, 3H). LCMS [M+1] ⁺ : 485.1. 12-17

( R )-4-methyl- N -(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-7-(6-methyl-2,6-diazepine Spiro[3.4]oct-2-yl)pyrido[3,4- d ]ta

-1-amine hydrochloride ¹ H NMR (400 MHz, CD ₃ OD) δ = 9.25 (br s, 1H), 7.83-7.70 (m, 1H), 7.55 (br d, J = 7.6 Hz, 1H), 7.46-7.18 (m, 2H ), 5.57-5.48 (m, 1H), 4.84-4.68 (m, 1H), 4.55-4.27 (m, 3H), 4.07-4.01 (m, 1H), 3.99-3.67 (m, 2H), 3.58-3.43 (m, 1H), 3.03 (s, 3H), 2.79 (s, 3H), 2.71-2.48 (m, 5H), 1.69 (d, J = 7.2 Hz, 3H). LCMS [M+1] ⁺ : 471.2. 12-18

( R )-7-(4-(dimethylamino)-4-methylpiperidin-1-yl)-4-methyl- N -(1-(2-methyl-3-(trifluoro (Methyl) phenyl) ethyl) pyrido[3,4- d ]

-1-amine ¹ H NMR (400 MHz, CD ₃ OD) δ = 9.26 (s, 1H), 7.77 (t, J = 4.0 Hz, 2H), 7.55 (d, J = 7.6 Hz, 1H), 7.31 (t, J = 8.0 Hz, 1H), 5.53 (q, J = 6.8 Hz, 1H), 4.99-4.92 (m, 2H), 3.46-3.36 (m, 2H), 2.89 (s, 6H), 2.80 (s, 3H), 2.64 (s, 3H), 2.22 (br d, J = 12.4 Hz, 2H), 2.07-1.96 (m, 2H), 1.71 (d, J = 6.8 Hz, 3H), 1.61 (s, 3H). LCMS [M+1] ⁺ : 487.2. 12-19

( R )-7-(3-(dimethylamino)-3-methylazetidin-1-yl)-4-methyl- N -(1-(2-methyl-3- (Trifluoromethyl)phenyl)ethyl)pyrido[3,4- d ]

-1-amine ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 8.93 (s, 1H), 7.72 (d, J = 7.6 Hz, 1H), 7.52 (d, J = 7.2 Hz, 1H), 7.45 (d, J = 6.8 Hz, 1H), 7.31 (t, J = 8.0 Hz, 1H), 7.09 (s, 1H), 5.68-5.57 (m, 1H), 3.94-3.86 (m, 2H), 3.80 (dd, J = 3.2, 8.0 Hz, 2H), 2.55 (br s, 3H), 2.54 (s, 3H), 2.15 (s, 6H), 1.53 (d, J = 7.2 Hz, 3H), 1.32 (s, 3H). LCMS [M+1] ⁺ : 459.4. 12-20

( R )-7-(3-(dimethylamino)azetidin-1-yl)-4-methyl- N -(1-(2-methyl-3-(trifluoromethyl )Phenyl)ethyl)pyrido[3,4- d ]

-1-amine hydrochloride ¹ H NMR (400 MHz, CD ₃ OD) δ = 9.27 (s, 1H), 7.71 (d, J = 7.2 Hz, 1H), 7.54 (d, J = 7.6 Hz, 1H), 7.44 (s, 1H) , 7.32-7.27 (m, 1H), 5.52 (q, J =7.2 Hz, 1H), 4.72-4.65 (m, 2H), 4.55 (m, 2H), 4.42 (br s, 1H), 3.01 (s, 6H), 2.80 (s, 3H), 2.62 (s, 3H), 1.68 (d, J =7.2 Hz, 3H). LCMS [M+1] ⁺ : 445.2. 12-21

( R )-3-methyl-1-(4-methyl-1-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyrido(3 ,4- d ]

-7-yl)azetidin-3-ol ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 8.94 (s, 1H), 7.72 (d, J = 8.0 Hz, 1H), 7.49 (dd, J = 7.6, 18.8 Hz, 2H), 7.31 (t , J = 8.0 Hz, 1H), 7.08 (s, 1H), 5.71 (s, 1H), 5.62 (t, J = 6.8 Hz, 1H), 4.04-3.92 (m, 4H), 2.55 (s, 3H) , 2.54 (s, 3H), 1.54 (d, J = 6.8 Hz, 3H), 1.49 (s, 3H). LCMS [M+1] ⁺ : 432.2. 12-22

( R )-1-(4-methyl-1-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyrido[3,4- d ] despair

-7-yl)azetidin-3-ol ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 14.76 (br s, 1H), 9.19 (s, 1H), 8.97 (br d, J = 3.6 Hz, 1H), 7.85 (d, J = 8.0 Hz , 1H), 7.60-7.53 (m, 2H), 7.35 (t, J = 8.0 Hz, 1H), 5.42 (br t, J = 6.8 Hz, 1H), 4.76-4.68 (m, 1H), 4.55-4.44 (m, 2H), 4.08-3.98 (m, 2H), 2.74 (s, 3H), 2.56 (s, 3H), 1.62 (d, J = 7.2 Hz, 3H). LCMS [M+1] ⁺ : 418.1. 12-23

3-((1 R )-1-((7-(6-oxa-3-azabicyclo[3.1.1]hept-3-yl)-4-methylpyrido[3,4- d ] despair

-1-yl)amino)ethyl)-2-methylbenzonitrile ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 9.04 (s, 1H), 8.14 (s, 1H), 7.73 (d, J = 7.6 Hz, 1H), 7.64-7.57 (m, 2H), 7.31 (t, J = 7.6 Hz, 1H), 7.26 (s, 1H), 5.56-5.52 m, 1H), 4.80 (d, J = 6.0 Hz, 2H), 3.91-3.87 (m, 2H), 3.74-3.68 (m, 2H), 3.20 (d, J = 8.4 Hz, 2H), 2.66 (s, 3H), 2.57 (s, 3H), 1.95 (d, J = 9.2 Hz, 1H), 1.55 (d, J = 7.2 Hz, 3H). LCMS [M+1] ⁺ : 401.3. 12-24

3-(( R )-1-((7-((1 R ,4 R )-2-oxa-5-azabicyclo[2.2.1]hept-5-yl)-4-methylpyrido [3,4- d ]

-1-yl)amino)ethyl)-2-methylbenzonitrile formate ¹ H NMR (400 MHz, CD ₃ OD) δ = 9.10 (s, 1H), 8.47 (s, 1H), 7.70 (d, J = 7.6 Hz, 1H), 7.52 (d, J = 7.6 Hz, 1H) , 7.28 (t, J = 7.6 Hz, 1H), 7.20 (s, 1H), 5.49-5.43 (m, 1H), 5.24 (s, 1H), 4.85-4.83 (m, 1H), 4.83 (s, 2H) ), 3.96 (d, J = 7.6 Hz, 1H), 3.85 (d, J = 7.6 Hz, 1H), 3.69 (d, J = 10.4 Hz, 1H), 3.55 (d, J = 10.8 Hz, 1H), 2.71 (s, 3H), 2.71 (s, 3H), 2.09 (s, 2H), 1.63 (d, J = 7.2 Hz, 3H). LCMS [M+1] ⁺ : 401.3. 12-25

( R )-2-methyl-3-(1-((4-methyl-7-(piper

-1-yl)pyrido[3,4- d ]

-1-yl)amino)ethyl)benzonitrile hydrochloride ¹ H NMR (400 MHz, CD ₃ OD) δ = 9.30 (s, 1H), 7.87 (s, 1H), 7.82 (d, J = 7.2 Hz, 1H), 7.55 (d, J = 6.8 Hz, 1H) , 7.30 (t, J = 8.0 Hz, 1H), 7.34-7.26 (m, 1H), 5.44 (q, J = 6.8 Hz, 1H), 4.35-4.26 (m, 4H), 3.49-3.40 (m, 4H ), 2.82 (s, 3H), 2.74 (s, 3H), 1.70 (d, J = 7.2 Hz, 3H). LCMS [M+1] ⁺ : 388.2. 12-26

4-methyl- N -(( R )-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-7-((1 R ,4 R )-5-methyl -2,5-diazabicyclo[2.2.2]oct-2-yl)pyrido[3,4- d ]

-1-carbamate ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 8.94 (s, 1H), 8.17 (s, 1H), 7.73 (d, J = 8.0 Hz, 1H), 7.56-7.45 (m, 2H), 7.32 (t, J = 7.6 Hz, 1H), 7.11 (s, 1H), 5.70-5.58 (m, 1H), 4.88-4.69 (m, 1H), 3.86 (d, J = 11.2 Hz, 1H), 3.05- 2.99 (m, 2H), 2.93-2.85 (m, 1H), 2.56 (s, 3H), 2.54 (s, 3H), 2.43 (s, 3H), 2.16-2.03 (m, 1H), 1.88-1.79 ( m, 2H), 1.72-1.63 (m, 1H), 1.55 (d, J = 6.8 Hz, 3H). LCMS [M+1] ⁺ : 471.2. 12-27

3-(( R )-1-((7-(( S )-hexahydropyridine

And [2,1-c][1,4]

-8(1 H )-yl)-4-methylpyrido[3,4- d ]

-1-yl)amino)ethyl)-2-methylbenzonitrile ¹ H NMR (400 MHz, CD ₃ OD) δ = 9.02 (s, 1H), 7.72 (d, J = 7.6 Hz, 1H), 7.51 (dd, J = 1.2, 7.6 Hz, 1H), 7.34 (s, 1H), 7.27 (t, J = 8.0 Hz, 1H), 5.60 (q, J = 6.8 Hz, 1H), 4.63 (br d, J = 13.6 Hz, 1H), 4.42 (br d, J = 12.8 Hz, 1H), 3.94-3.83 (m, 2H), 3.75 (dt, J = 2.4, 11.6 Hz, 1H), 3.39 (t, J = 10.8 Hz, 1H), 3.18 (dt, J = 3.2, 12.8 Hz, 1H ), 2.97 (br d, J = 11.6 Hz, 1H), 2.81 (br d, J = 11.6 Hz, 1H), 2.77-2.71 (m, 3H), 2.71-2.66 (m, 1H), 2.64 (s, 3H), 2.48-2.32 (m, 3H), 1.63 (d, J = 6.8 Hz, 3H). LCMS [M+1] ⁺ : 444.2. 12-28

( R )-3-(1-((7-(4-(dimethylamino)piperidin-1-yl)-4-methylpyrido[3,4- d ]

-1-yl)amino)ethyl)-2-methylbenzonitrile hydrochloride ¹ H NMR (400 MHz, CD ₃ OD) δ = 9.25 (s, 1H), 7.77 (d, J = 8.0 Hz, 1H), 7.72 (s, 1H), 7.55 (d, J = 7.6 Hz, 1H) , 7.33-7.27 (m, 1H), 5.43 (q, J = 6.8 Hz, 1H), 5.12-5.01 (m, 2H), 3.72-3.59 (m, 1H), 3.24 (br t, J = 12.4 Hz, 2H), 2.92 (s, 6H), 2.79 (s, 3H), 2.74 (s, 3H), 2.32 (br d, J = 11.6 Hz, 2H), 1.89-1.75 (m, 2H), 1.68 (d, J = 6.8 Hz, 3H). LCMS [M+1] ⁺ : 430.3. 12-29

( R )-3-(1-((7-(4-(azetidin-1-yl)piperidin-1-yl)-4-methylpyrido[3,4- d ]

-1-yl)amino)ethyl)-2-methylbenzonitrile hydrochloride ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 14.94-14.58 (m, 1H), 11.66-11.25 (m, 1H), 9.24 (s, 1H), 8.11 (s, 1H), 7.91 (d, J = 8.0 Hz, 1H), 7.65 (d, J = 7.6 Hz, 1H), 7.36 (t, J = 8.0 Hz, 1H), 5.33 (t, J = 6.8 Hz, 1H), 4.90 (br d, J = 13.2 Hz, 2H), 4.21-3.92 (m, 4H), 3.55 (br s, 1H), 3.18 (br t, J = 12.8 Hz, 2H), 2.74 (s, 3H), 2.67 (s, 3H) , 2.44-2.19 (m, 2H), 2.08 (br d, J = 10 Hz, 2H), 1.64 (d, J = 6.8 Hz, 3H), 1.53-1.40 (m, 2H). LCMS [M+1] ⁺ : 442.3. 12-30

( R )-3-(1-((7-(3-hydroxy-3-methylazetidin-1-yl)-4-methylpyrido[3,4- d ]

-1-yl)amino)ethyl)-2-methylbenzonitrile ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 14.80 (br s, 1H), 9.19 (s, 1H), 9.04 (br d, J = 3.6 Hz, 1H), 7.87 (d, J = 8.0 Hz , 1H), 7.69-7.59 (m, 2H), 7.39-7.31 (m, 1H), 5.37-5.24 (m, 1H), 4.21-4.05 (m, 4H), 2.74 (s, 3H), 2.66 (s , 3H), 1.62 (br d, J = 7.2 Hz, 3H), 1.49 (s, 3H). LCMS [M+1] ⁺ : 389.2. 12-31

7-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-4-methyl- N -(( R )-1-(2-methyl-3-(trifluoro (Methyl) phenyl) ethyl) pyrido[3,4- d ]

-1-amine hydrochloride ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 14.65 (s, 1H), 9.26 (s, 1H), 8.88 (s, 1H), 7.88 (s, 1H), 7.82 (d, J = 8.0 Hz , 1H), 7.56 (d, J = 7.6 Hz, 1H), 7.36 (t, J = 7.6 Hz, 1H), 5.47-5.37 (m, 1H), 4.94 (s, 2H), 3.79-3.61 (m, 4H), 2.73 (s, 3H), 2.56 (s, 3H), 2.18-1.94 (m, 4H), 1.62 (d, J = 6.8 Hz, 3H). LCMS [M+1] ⁺ : 458.1. 12-32

( R )-2-(4-methyl-1-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyrido[3,4-d] despair

-7-yl)-2,6-diazaspiro[3.4]octan-5-one ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.24 (s, 1H), 8.78 (s, 1H), 7.94 (s, 1H), 7.76 (d, J = 7.9 Hz, 1H), 7.55 (d, J = 7.8 Hz, 1H), 7.49 (s, 1H), 7.34 (t, J = 7.8 Hz, 1H), 5.46-5.35 (m, 1H), 4.40-4.14 (m, 5H), 3.23 (t, J = 6.7 Hz, 2H), 2.72 (s, 3H), 2.54 (s, 3H), 1.59 (d, J = 6.9 Hz, 4H). LCMS [M+1] ⁺ : 471.1. 12-33

( R )-7-(4-(azetidin-1-yl)piperidin-1-yl)-4-methyl- N -(1-(2-methyl-3-(trifluoromethyl (Yl)phenyl)ethyl)pyrido[3,4- d ]ta

-1-amine ¹ H NMR (400 MHz, methanol- d ₄ ) δ 9.23 (s, 1H), 7.77-7.70 (m, 2H), 7.53 (d, J = 7.8 Hz, 1H), 7.29 (t, J = 7.8 Hz, 1H), 5.51 (q, J = 6.9 Hz, 1H), 5.04-4.95 (m, 2H), 4.34-4.15 (m, 4H), 3.67 (d, J = 12.0 Hz, 1H), 3.25 (t, J = 13.1 Hz, 2H), 2.78 (s, 3H), 2.70-2.59 (m, 4H), 2.47-2.35 (m, 1H), 2.23 (d, J = 12.5 Hz, 2H), 1.68 (d, J = 6.9 Hz, 3H), 1.62-1.48 (m, 2H). LCMS [M+1] ⁺ : 485.2. 12-34

( R )-3-(1-((7-(4,4-difluoropiperidin-1-yl)-4-methylpyrido[3,4- d ]

-1-yl)amino)ethyl)-2-methylbenzonitrile ¹ H NMR (400 MHz, methanol- d ₄ ) δ 9.06 (d, J = 0.8 Hz, 1H), 7.73 (dd, J = 7.9, 1.3 Hz, 1H), 7.52 (dd, J = 7.7, 1.3 Hz, 1H), 7.48 (d, J = 0.9 Hz, 1H), 7.28 (t, J = 7.8 Hz, 1H), 5.58 (q, J = 7.0 Hz, 1H), 4.03 (t, J = 5.8 Hz, 5H) , 2.75 (s, 3H), 2.66 (s, 3H), 2.11 (ddt, J = 19.0, 13.5, 5.7 Hz, 5H), 1.64 (d, J = 7.0 Hz, 3H). LCMS [M+1] ⁺ : 423.2. 12-35

( R )-2-Methyl-3-(1-((4-methyl-7-(6-methyl-5-oxo-2,6-diazaspiro[3.4]oct-2- Yl)pyrido[3,4- d ]

-1-yl)amino)ethyl)benzonitrile ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.96 (s, 1H), 7.72 (d, J = 7.8 Hz, 1H), 7.60 (dd, J = 7.6, 1.3 Hz, 1H), 7.49 (d, J = 6.8 Hz, 1H), 7.31 (t, J = 7.8 Hz, 1H), 7.09 (s, 1H), 5.52 (q, J = 7.0 Hz, 1H), 4.19 (dd, J = 8.3, 5.1 Hz, 2H), 4.05 (dd, J = 8.0, 1.7 Hz, 2H), 2.79 (s, 3H), 2.68-2.64 (m, 4H), 2.55 (s, 3H), 2.43 (t, J = 6.8 Hz, 2H ), 2.33 (p, J = 1.8 Hz, 1H), 1.53 (d, J = 7.0 Hz, 3H). LCMS [M+1] ⁺ : 442.2. 12-36

( R )-2-methyl-3-(1-((4-methyl-7-(4-(1-methyl-1 H -pyrazol-4-yl)piper

-1-yl)pyrido[3,4- d ]

-1-yl)amino)ethyl)benzonitrile ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.00 (s, 1H), 7.71 (dd, J = 8.0, 1.4 Hz, 1H), 7.61 (dd, J = 7.6, 1.3 Hz, 1H), 7.55 ( d, J = 6.8 Hz, 1H), 7.46 (s, 1H), 7.36 (s, 1H), 7.32 (t, J = 7.8 Hz, 1H), 7.24 (d, J = 0.9 Hz, 1H), 5.54 ( q, J = 6.7 Hz, 1H), 3.85 (t, J = 5.2 Hz, 4H), 3.75 (s, 3H), 3.01 (t, J = 5.2 Hz, 4H), 2.65 (s, 3H), 2.55 ( s, 3H), 1.55 (d, J = 7.0 Hz, 3H). LCMS [M+1] ⁺ : 468.3. 12-37

( R )-7-(3-Methoxy-3-methylazetidin-1-yl)-4-methyl- N -(1-(2-methyl-3-(trifluoromethyl (Yl)phenyl)ethyl)pyrido[3,4- d ]ta

-1-amine ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.85 (s, 1H), 8.54 (s, 1H), 7.65 (d, J = 7.9 Hz, 1H), 7.49 (d, J = 7.8 Hz, 1H), 7.18 (t, J = 7.8 Hz, 1H), 6.75 (s, 1H), 5.57 (q, J = 6.8 Hz, 1H), 4.25-4.16 (m, 2H), 4.09-4.00 (m, 2H), 3.32 ( s, 3H), 2.64 (s, 3H), 2.52 (s, 3H), 1.64 (d, J = 6.8 Hz, 3H), 1.59 (s, 3H). LCMS [M+1] ⁺ : 446.4. 12-38

( R )-7-(azetidin-1-yl)-4-methyl- N -(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)pyrido [3,4- d ]

-1-amine hydrochloride ¹ H NMR (400 MHz, CD ₃ OD) δ = 9.15 (s, 1H), 7.68 (d, J = 7.9 Hz, 1H), 7.54 (d, J = 7.8 Hz, 1H), 7.29 (t, J = 7.8 Hz, 1H), 7.16 (s, 1H), 5.49 (q, J = 7.0 Hz, 1H), 4.37 (t, J = 7.7 Hz, 5H), 2.75 (s, 3H), 2.68-2.50 (m, 5H), 1.65 (d, J = 7.0 Hz, 3H). LCMS [M+1] ⁺ : 402.2. 12-39

( R )-(3-methyl-1-(4-methyl-1-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyrido[ 3,4- d ]

-7-yl)azetidin-3-yl)methanol ¹ H NMR (400 MHz, CD ₃ OD) δ = 9.15 (d, J = 0.8 Hz, 1H), 7.69-7.65 (m, 1H), 7.55-7.51 (m, 1H), 7.29 (t, J = 7.9 Hz, 1H), 7.17 (d, J = 0.8 Hz, 1H), 5.49 (q, J = 6.9 Hz, 1H), 4.24-4.17 (m, 2H), 3.93 (dd, J = 9.6, 3.7 Hz, 2H ), 3.64 (s, 2H), 2.75 (s, 3H), 2.61 (d, J = 1.6 Hz, 3H), 1.65 (d, J = 7.0 Hz, 3H), 1.41 (s, 3H). LCMS [M+1] ⁺ : 446.2. 12-40

2-Methyl-3-(( R )-1-((4-methyl-7-((1 R ,4 R )-5-methyl-2,5-diazabicyclo[2.2.2] Oct-2-yl)pyrido[3,4- d ]

-1-yl)amino)ethyl)benzonitrile formate ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.94 (s, 1H), 8.16 (s, 1H), 7.72 (d, J = 7.6 Hz, 1H), 7.62 (d, J = 7.6 Hz, 1H ), 7.55-7.50 (m, 1H), 7.32 (t, J = 7.6 Hz, 1H), 7.09 (s, 1H), 5.55-5.51 (m, 1H), 4.81- 4.76 (m, 1H), 3.86- 3.83 (m, 1H), 3.47-3.44 (m, 1H), 3.02-3.00 (m, 2H), 2.90-2.85 (m, 1H), 2.66 (s, 3H), 2.54 (s, 3H), 2.41 ( s, 3H), 2.12-2.07 (m, 1H), 1.90-1.82 (m, 2H), 1.71-1.64 (m, 1H), 1.54 (d, J = 6.8 Hz, 3H). LCMS [M+1] ⁺ : 428.4. 12-41

( R )-4-methyl- N -(1-(2-methylpyridin-3-yl)ethyl)-7-

Hydroxypyrido[3,4- d ]

-1-amine ¹ H NMR (400 MHz, CD ₃ OD) δ 9.02 (d, J = 0.9 Hz, 1H), 8.22 (dd, J = 5.0, 1.7 Hz, 1H), 7.83 (dd, J = 7.9, 1.7 Hz, 1H) ), 7.31 (d, J = 1.0 Hz, 1H), 7.18 (dd, J = 7.9, 4.9 Hz, 1H), 5.59-5.53 (m, 1H), 3.86-3.81 (m, 4H), 3.79-3.73 ( m, 4H), 2.72 (s, 3H), 2.63 (s, 3H), 1.63 (d, J = 7.0 Hz, 3H). LCMS [M+1] ⁺ : 365.3. 12-42

N-(( R )-1-(3-(Difluoromethyl)-2-methylphenyl)ethyl)-7-(( S )-hexahydropyridine

And [2,1- c ][1,4]

-8(1 H )-yl)-4-methylpyrido[3,4- d ]

-1-carbamate ¹ H NMR (400 MHz, DMSO- d ₆ ): δ = 8.96 (s, 1H), 8.19 (s, 1H), 7.58 (d, J = 7.6 Hz, 1H), 7.45 (d, J = 7.2 Hz, 1H), 7.40 (s, 1H), 7.39-7.33 (m, 1H), 7.29-7.05 (m, 2H), 5.65-5.61 (m, 1H), 4.51-4.26 (m, 2H), 3.83-3.77 ( m, 2H), 3.58-3.56 (m, 1H), 3.23 (t, J = 10.8, 1H), 3.06 (dt, J = 12.4, 2.8 Hz, 1H), 2.91 (d, J = 11.2 Hz, 1H) , 2.72 (d, J = 11.2 Hz, 1H), 2.61-2.56 (m, 1H), 2.54 (s, 3H), 2.48 (s, 3H), 2.29-2.24 (m, 3H), 1.53 (d, J = 6.8 Hz, 3H). LCMS [M+1] ⁺ : 469.2. 12-43

( R )-3-(1-((7-(3-(dimethylamino)-3-methylazetidin-1-yl)-4-methylpyrido[3,4- d ]

-1-yl)amino)ethyl)-2-methylbenzonitrile hydrochloride ¹ H NMR (400 MHz, CD ₃ OD) δ = 9.26 (s, 1H), 7.79 (d, J = 8.0 Hz, 1H), 7.55 (d, J = 7.6 Hz, 1H), 7.49 (s, 1H) , 7.30 (t, J = 8.0 Hz, 1H), 5.43 (q, J = 7.2 Hz, 1H), 4.64 (br dd, J = 4.4, 10.4 Hz, 2H), 4.35 (dd, J = 4.4, 10.4 Hz) , 2H), 2.94 (s, 6H), 2.81 (s, 3H), 2.73 (s, 3H), 1.82 (s, 3H), 1.69 (d, J = 6.8 Hz, 3H). LCMS [M+1] ⁺ : 416.2. 12-44

(R)-2-methyl-3-(1-((4-methyl-7-(4-methylpiper

-1-yl)pyrido[3,4-d]ta

-1-yl)amino)ethyl)benzonitrile ¹ H NMR (400 MHz, CD ₃ OD) δ = 9.02 (s, 1H), 7.73 (d, J = 7.6 Hz, 1H), 7.51 (d, J = 8.0 Hz, 1H), 7.36 (s, 1H) , 7.27 (t, J = 8.0 Hz, 1H), 5.59 (q, J = 7.2 Hz, 1H), 3.85 (s, 4H), 2.75 (s, 3H), 2.68-2.56 (m, 7H), 2.40 ( s, 3H), 1.63 (d, J = 6.8 Hz, 3H). LCMS [M+1] ⁺ : 402.3. 12-45

( R )-3-(1-((7-(dimethylamino)-4-methylpyrido[3,4- d ]

-1-yl)amino)ethyl)-2-methylbenzonitrile ¹ H NMR (400 MHz, CD ₃ OD) δ = 8.96 (s, 1H), 7.72 (d, J = 8.0 Hz, 1H), 7.49 (d, J = 7.6 Hz, 1H), 7.25 (t, J = 7.6 Hz, 1H), 7.12 (s, 1H), 5.58 (q, J = 7.2 Hz, 1H), 3.27 (s, 6H), 2.73 (s, 3H), 2.60 (br s, 3H), 1.62 (d , J = 6.8 Hz, 3H). LCMS [M+1] ⁺ : 347.2. 12-46

( R )-3-(1-((7-(4-(dimethylamino)-4-methylpiperidin-1-yl)-4-methylpyrido[3,4- d ]

-1-yl)amino)ethyl)-2-methylbenzonitrile ¹ H NMR (400 MHz, CD ₃ OD) δ = 8.99 (s, 1H), 7.73 (d, J = 7.6 Hz, 1H), 7.51 (d, J = 7.6 Hz, 1H), 7.33 (s, 1H) , 7.27 (t, J = 7.6 Hz, 1H), 5.60 (q, J = 6.8 Hz, 1H), 4.27 (br d, J = 13.2 Hz, 2H), 3.45 (ddd, J = 4.4, 8.8, 13.2 Hz , 2H), 2.75 (s, 3H), 2.63 (s, 3H), 2.31 (s, 6H), 1.85-1.71 (m, 4H), 1.63 (d, J = 7.2 Hz, 3H), 1.15 (s, 3H). LCMS [M+1] ⁺ : 444.5. 12-47

( R )-1-(1-((1-(2,4-Difluorophenyl)ethyl)amino)-4-methylpyrido[3,4- d ]

-7-yl)-3-methylazetidine-3-ol ¹ H NMR (400 MHz, DMSO- d ₆ ): δ = 8.95 (s, 1H), 7.44-7.38 (m, 1H), 7.36 (d, J = 7.6 Hz, 1H), 7.23-7.12 (m, 1H) ), 7.06 (s, 1H), 7.01-6.93 (m, 1H), 5.71 (s, 1H), 5.62-5.52 (m, 1H), 4.05-3.90 (m, 4H), 2.54 (s, 3H), 1.55 (d, J = 7.2 Hz, 3H), 1.49 (s, 3H). LCMS [M+1] ⁺ : 386.1. 12-48

N -(( R )-1-(2,4-difluorophenyl)ethyl)-7-(( S )-hexahydropyridine

And [2,1- c ][1,4]

-8(1 H )-yl)-4-methylpyrido[3,4- d ]

-1-carbamate ¹ H NMR (400 MHz, DMSO- d ₆ ): δ = 8.99 (s, 1H), 8.15 (s, 1H), 7.47-7.31 (m, 3H), 7.25-7.12 (m, 1H), 7.04-6.91 (m, 1H), 5.59 (t, J = 6.8 Hz, 1H), 4.49-4.31 (m, 2H), 3.88-3.74 (m, 2H), 3.61-3.54 (m, 1H), 3.24-3.21 (m , 1H), 3.12-3.04 (m, 1H), 2.92 (d, J = 10.8 Hz, 1H), 2.73 (d, J = 11.6 Hz, 1H), 2.63-2.57 (m, 1H), 2.57-2.53 ( m, 3H), 2.29-2.15 (m, 3H), 1.57 (d, J = 7.2 Hz, 3H). LCMS [M+1] ⁺ : 441.4. 12-49

( R ) -N -(1-(2,4-Difluorophenyl)ethyl)-7-(3-(dimethylamino)-3-methylazetidine-1-yl) -4-methylpyrido[3,4- d ]

-1-carbamate ¹ H NMR (400 MHz, DMSO- d ₆ ): δ = 8.95 (s, 1H), 8.16 (s, 1H), 7.45-7.32 (m, 2H), 7.22 -7.14 (m, 1H), 7.08 (s , 1H), 7.01-6.93 (m, 1H), 5.57 (t, J = 6.8 Hz, 1H), 3.93-3.86 (m, 2H), 3.79 (d, J = 8.0 Hz, 2H), 2.55 (s, 3H), 2.15 (s, 6H), 1.56 (d, J = 7.2 Hz, 3H), 1.32 (s, 3H). LCMS [M+1] ⁺ : 413.4. 12-50

( R ) -N -(1-(2-Fluoro-3-(trifluoromethyl)phenyl)ethyl)-4-methyl-7-

Hydroxypyrido[3,4- d ]

-1-amine ¹ H NMR (400 MHz, CD ₃ OD) δ = 9.03 (d, J = 0.8 Hz, 1H), 7.65 (t, J = 6.8 Hz, 1H), 7.51 (t, J = 7.2 Hz, 1H), 7.37 (s, 1H), 7.21 (t, J = 7.6 Hz, 1H), 5.68 (q, J = 7.2 Hz, 1H), 3.88-3.83 (m, 4H), 3.81-3.76 (m, 4H), 2.62 ( s, 3H), 1.68 (d, J = 7.2 Hz, 3H). LCMS [M+1] ⁺ : 436.2. 12-51

( R )-2-Methyl-3-(1-((4-methyl-7-(6-methyl-2,6-diazaspiro[3.4]oct-2-yl)pyrido[3 ,4- d ]

-1-yl)amino)ethyl)benzonitrile ¹ H NMR (400 MHz, CD ₃ OD) δ = 8.92 (s, 1H), 7.70 (d, J = 8.0 Hz, 1H), 7.49 (d, J = 8.0 Hz, 1H), 7.29-7.21 (m, 1H), 7.00 (s, 1H), 5.57 (q, J = 6.8 Hz, 1H), 4.21-4.14 (m, 2H), 4.14-4.06 (m, 2H), 2.88 (s, 2H), 2.75 (s , 3H), 2.69 (t, J = 7.2 Hz, 2H), 2.61 (s, 3H), 2.41 (s, 3H), 2.25 (t, J = 7.2 Hz, 2H), 1.61 (d, J = 7.2 Hz , 3H). LCMS [M+1] ⁺ : 428.2. 12-52

( R )-3-(1-((7-(4-ethylpiper

-1-yl)-4-methylpyrido[3,4- d ]

-1-yl)amino)ethyl)-2-methylbenzonitrile ¹ H NMR (400 MHz, CD ₃ OD) δ = 9.30 (s, 1H), 7.91 (s, 1H), 7.83 (d, J = 7.6 Hz, 1H), 7.55 (d, J = 7.6 Hz, 1H) , 7.30 (t, J = 8.0 Hz, 1H), 5.44 (q, J = 6.8 Hz, 1H), 5.08 (br d, J = 14.4 Hz, 2H), 3.80 (br d, J = 12.0 Hz, 2H) , 3.63 (br t, J = 12.8 Hz, 2H), 3.33 (s, 2H), 3.24 (br s, 2H), 2.82 (s, 3H), 2.74 (s, 3H), 1.70 (d, J = 6.8 Hz, 3H), 1.45 (t, J = 7.2 Hz, 3H). LCMS [M+1] ⁺ : 416.2. 12-53

( R )-3-(1-((7-(4-hydroxy-4-methylpiperidin-1-yl)-4-methylpyrido[3,4- d ]

-1-yl)amino)ethyl)-2-methylbenzonitrile ¹ H NMR (400 MHz, CD ₃ OD) δ = 8.95 (s, 1H), 7.70 (d, J = 7.6 Hz, 1H), 7.48 (d, J = 6.8 Hz, 1H), 7.31 (s, 1H) , 7.24 (t, J = 8.0 Hz, 1H), 5.61-5.49 (m, 1H), 4.23-4.13 (m, 2H), 3.63-3.52 (m, 2H), 2.72 (s, 3H), 2.59 (s , 3H), 1.73-1.64 (m, 4H), 1.60 (d, J = 6.8 Hz, 3H), 1.28 (s, 3H). LCMS [M+1] ⁺ : 417.3. 12-54

( R )-3-(1-((7-(3-(dimethylamino)azetidin-1-yl)-4-methylpyrido[3,4- d ]

-1-yl)amino)ethyl)-2-methylbenzonitrile hydrochloride ¹ H NMR (400 MHz, CD ₃ OD) δ = 9.26 (s, 1H), 7.80 (d, J = 7.2 Hz, 1H), 7.57-7.52 (m, 1H), 7.50 (s, 1H), 7.30 ( t, J = 8.0 Hz, 1H), 5.43 (q, J = 6.8 Hz, 1H), 4.77-4.63 (m, 2H), 4.62-4.51 (m, 2H), 4.44 (tt, J = 4.8, 7.6 Hz , 1H), 3.00 (s, 6H), 2.81 (s, 3H), 2.73 (s, 3H), 1.69 (d, J = 6.8 Hz, 3H). LCMS [M+1] ⁺ : 402.2. 12-55

( R )-3-(1-((7-(3-methoxy-3-methylazetidin-1-yl)-4-methylpyrido[3,4- d ]

-1-yl)amino)ethyl)-2-methylbenzonitrile ¹ H NMR (400 MHz, CD ₃ OD) δ = 9.18 (s, 1H), 7.71 (d, J = 7.2 Hz, 1H), 7.55 (d, J = 6.8 Hz, 1H), 7.30 (t, J = 7.6 Hz, 1H), 7.21 (s, 1H), 5.40 (q, J = 6.8 Hz, 1H), 4.25 (dd, J = 2.8, 9.8 Hz, 2H), 4.13 (dd, J = 1.6, 10.0 Hz, 2H), 3.35 (s, 3H), 2.77 (s, 3H), 2.73 (s, 3H), 1.65 (d, J = 7.2 Hz, 3H), 1.62 (s, 3H). LCMS [M+1] ⁺ : 403.2. 12-56

( R )-1-(1-((1-(2,3-Difluorophenyl)ethyl)amino)-4-methylpyrido[3,4- d ]

-7-yl)-3-methylazetidine-3-ol ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 8.95 (s, 1H), 7.42 (d, J = 6.8 Hz, 1H), 7.27-7.17 (m, 2H), 7.14-7.05 (m, 2H) , 5.71 (s, 1H), 5.65-5.58 (m, 1H), 4.05-3.94 (m, 4H), 2.55 (s, 3H), 1.60 (d, J = 6.8 Hz, 3H), 1.49 (s, 3H) ). LCMS [M+1] ⁺ : 386.0. 12-57

( R )-1-(1-((1-(4-Fluoro-2-methylphenyl)ethyl)amino)-4-methylpyrido[3,4- d ]

-7-yl)-3-methylazetidine-3-ol ¹ H NMR (400 MHz, CD ₃ OD) δ = 8.92 (s, 1H), 7.41 (dd, J = 6.0, 8.4 Hz, 1H), 7.01 (s, 1H), 6.90-6.77 (m, 2H), 5.56 (q, J = 6.8 Hz, 1H), 4.12-3.98 (m, 4H), 2.63 (s, 3H), 2.47 (s, 3H), 1.62-1.55 (m, 6H). LCMS [M+1] ⁺ : 382.1. 12-58

7-(6-oxa-3-azabicyclo[3.1.1]heptan-3-yl) -N -(( R )-1-(2,4-difluorophenyl)ethyl)-4- Pico[3,4- d]

-1-amine ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 9.05 (s, 1H), 7.49-7.38 (m, 3H), 7.26 (s, 2H), 7.21-7.15 (m, 1H), 6.98 (t, J = 8.7 Hz, 1H), 5.62 (t, J = 7.0 Hz, 1H), 4.84-4.78 (m, 2H), 3.93-3.86 (m, 2H), 3.79-3.69 (m, 2H), 3.24-3.17 (m, 1H), 2.58 (s, 3H), 1.95 (d, J = 8.8 Hz, 1H), 1.58 (d, J = 7.1 Hz, 3H). LCMS [M+1] ⁺ : 398.1. 12-59

( R )-N-(1-(3-(Difluoromethyl)-2-methylphenyl)ethyl)-4-methyl-7-(4-(1-methyl-1 H -pyridine (Azol-4-yl)piperidine

-1-yl)pyrido[3,4- d ]

-1-amine ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.99 (s, 1H), 7.62-7.18 (m, 7H), 5.64 (t, J = 6.9 Hz, 1H), 3.88-3.81 (m, 4H), 3.75 (s, 3H), 3.04-2.97 (m, 4H), 2.55 (s, 3H), 1.54 (d, J = 6.9 Hz, 3H). LCMS [M+1] ⁺ : 493.3. 12-60

N -(( R )-1-(2-Fluoro-3-(trifluoromethyl)phenyl)ethyl)-4-methyl-7-((1 R ,4 R )-5-methyl- 2,5-diazabicyclo[2.2.2]oct-2-yl)pyrido[3,4- d ]ta

-1-carbamate ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 8.94 (s, 1H), 7.69 (t, J = 7.2 Hz, 1H), 7.61 (t, J = 7.2 Hz, 1H), 7.47 (d, J = 7.0 Hz, 1H), 7.31 (t, J = 7.8 Hz, 1H), 7.11 (s, 1H), 5.70-5.59 (m, 1H), 3.84 (d, J = 11.2 Hz, 1H), 3.45 (d , J = 11.1 Hz, 1H), 3.00-2.77 (m, 4H), 2.37 (s, 3H), 2.13-1.96 (m, 2H), 1.87-1.79 (m, 2H), 1.61 (d, J = 7.0 Hz, 3H). LCMS [M+1] ⁺ : 475.0. 12-61

( R )-1-(1-((1-(2-Fluoro-3-(trifluoromethyl)phenyl)ethyl)amino)-4-methylpyrido[3,4- d ]

-7-yl)-3-methylazetidine-3-ol ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 8.96 (s, 1H), 7.69 (t, J = 7.3 Hz, 1H), 7.61 (t, J = 7.2 Hz, 1H), 7.48 (d, J = 7.0 Hz, 1H), 7.30 (t, J = 7.8 Hz, 1H), 7.08 (s, 1H), 5.67-5.59 (m, 1H), 4.05-3.93 (m, 4H), 2.54 (s, 3H) , 1.60 (d, J = 7.0 Hz, 3H), 1.50 (s, 3H). LCMS [M+1] ⁺ : 436.1. 12-62

( R )-7-(3-(dimethylamino)-3-methylazetidin-1-yl) -N -(1-(2-fluoro-3-(trifluoromethyl) (Phenyl) ethyl)-4-methylpyrido[3,4- d ]

-1-carbamate ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.08 (s, 1H), 7.90 (s, 1H), 7.73 (t, J = 7.4 Hz, 1H), 7.64 (t, J = 7.3 Hz, 1H) , 7.33 (t, J = 7.8 Hz, 1H), 7.21 (s, 1H), 5.63-5.54 (m, 1H), 4.06 (d, J = 9.0 Hz, 2H), 3.91 (d, J = 8.8 Hz, 2H), 2.62 (s, 3H), 2.29 (s, 6H), 1.63 (d, J = 7.0 Hz, 3H), 1.41 (s, 3H). LCMS [M+1] ⁺ : 463.3. 12-63

N -(( R )-1-(2-fluoro-3-(trifluoromethyl)phenyl)ethyl)-7-(( S )-hexahydropyridine

And [2,1- c ][1,4]

-8(1 H )-yl)-4-methylpyrido[3,4- d ]

-1-amine ¹ H NMR (400 MHz, methanol- d ₄ ) δ 9.02 (s, 1H), 7.65 (t, J = 7.4 Hz, 1H), 7.51 (t, J = 7.2 Hz, 1H), 7.37 (s, 1H) , 7.21 (t, J = 7.8 Hz, 1H), 5.68 (q, J = 7.1 Hz, 1H), 4.63 (d, J = 13.3 Hz, 1H), 4.43 (d, J = 12.8 Hz, 1H), 3.93 -3.71 (m, 3H), 3.38 (t, J = 10.7 Hz, 1H), 3.24-3.11 (m, 1H), 2.97 (d, J = 11.4 Hz, 1H), 2.80 (d, J = 11.6 Hz, 1H), 2.71 (t, J = 11.7 Hz, 1H), 2.62 (s, 3H), 2.47-2.33 (m, 3H), 1.68 (d, J = 7.0 Hz, 3H). LCMS [M+1] ⁺ : 491.4. 12-64

( R )-7-(4-(dimethylamino)piperidin-1-yl) -N -(1-(2-fluoro-3-(trifluoromethyl)phenyl)ethyl)-4 -Methylpyrido[3,4- d ]ta

-1-carbamate ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 8.99 (s, 1H), 7.70 (t, J = 7.4 Hz, 1H), 7.62 (t, J = 7.3 Hz, 1H), 7.57 (d, J = 6.8 Hz, 1H), 7.47 (s, 1H), 7.31 (t, J = 7.7 Hz, 1H), 5.69-5.60 (m, 1H), 4.64 (d, J = 13.2 Hz, 2H), 3.02 (t , J = 12.6 Hz, 2H), 2.88-2.75 (m, 1H), 2.55 (s, 3H), 2.41 (s, 6H), 2.04-1.94 (m, 2H), 1.62 (d, J = 7.0 Hz, 3H), 1.49 (q, J = 12.4 Hz, 2H). LCMS [M+1] ⁺ : 477.3. 12-65

( R ) -N -(1-(2-Fluoro-3-(trifluoromethyl)phenyl)ethyl)-4-methyl-7-(piper

-1-yl)pyrido[3,4- d ]

-1-amine ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.02 (s, 1H), 7.70 (t, J = 7.4 Hz, 1H), 7.62 (t, J = 7.2 Hz, 1H), 7.56 (s, 1H) , 7.48 (s, 1H), 7.31 (t, J = 7.8 Hz, 1H), 5.69-5.60 (m, 1H), 3.85-3.77 (m, 4H), 3.10-3.02 (m, 4H), 2.56 (s , 3H), 1.62 (d, J = 7.0 Hz, 3H). LCMS [M+1] ⁺ : 435.3. 12-66

( R )-7-(3-(dimethylamino)azetidin-1-yl) -N -(1-(2-fluoro-3-(trifluoromethyl)phenyl)ethyl )-4-methylpyrido[3,4- d ]

-1-amine ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 8.96 (s, 1H), 7.70 (t, J = 7.4 Hz, 1H), 7.61 (t, J = 7.3 Hz, 1H), 7.48 (d, J = 6.9 Hz, 1H), 7.30 (t, J = 7.8 Hz, 1H), 7.10 (s, 1H), 5.68-5.59 (m, 1H), 4.21-4.13 (m, 2H), 3.94-3.86 (m, 2H), 2.55 (s, 2H), 2.16 (s, 5H), 1.60 (d, J = 7.0 Hz, 3H). LCMS [M+1] ⁺ : 449.3. 12-67

( R ) -N -(1-(2-Fluoro-3-(trifluoromethyl)phenyl)ethyl)-4-methyl-7-(4-methylpiper

-1-yl)pyrido[3,4- d ]

-1-amine ¹ H NMR (400 MHz, CD ₃ OD) δ = 9.12 (s, 1H), 8.47 (s, 1H), 7.68 (t, J = 7.3 Hz, 1H), 7.54 (t, J = 7.3 Hz, 1H) , 7.47 (s, 1H), 7.24 (t, J = 7.8 Hz, 1H), 5.61 (q, J = 7.0 Hz, 1H), 3.95 (t, J = 5.2 Hz, 4H), 2.69 (d, J = 2.9 Hz, 7H), 2.44 (s, 3H), 1.70 (d, J = 7.0 Hz, 3H). LCMS [M+1] ⁺ : 449.0. 12-68

( R )-7-(4-ethylpiper

-1-yl) -N -(1-(2-fluoro-3-(trifluoromethyl)phenyl)ethyl)-4-methylpyrido[3,4- d ]

-1-amine ¹ H NMR (400 MHz, CD ₃ OD) δ = 9.10 (s, 1H), 7.69 (t, J = 7.4 Hz, 1H), 7.55 (t, J = 7.2 Hz, 1H), 7.44 (s, 1H) , 7.25 (t, J = 7.8 Hz, 1H), 5.66 (q, J = 7.0 Hz, 1H), 3.93 (t, J = 5.2 Hz, 4H), 2.73 (t, J = 5.2 Hz, 4H), 2.68 (s, 3H), 2.61 (q, J = 7.2 Hz, 2H), 1.71 (d, J = 7.0 Hz, 3H), 1.22 (t, J = 7.2 Hz, 3H). LCMS [M+1] ⁺ : 463.0. 12-69

3-(( R )-1-((7-(( S )-3-(dimethylamino)pyrrolidin-1-yl)-4-methylpyrido[3,4- d ]

-1-yl)amino)ethyl)-2-methylbenzonitrile ¹ H NMR (400 MHz, CD ₃ OD) δ 8.95 (d, J = 0.8 Hz, 1H), 7.71 (dd, J = 8.0, 1.4 Hz, 1H), 7.50 (d, J = 1.4 Hz, 0H), 7.24 (t, J = 7.8 Hz, 1H), 7.01 (s, 1H), 5.58 (q, J = 6.9 Hz, 1H), 3.97-3.83 (m, 3H), 3.61-3.49 (m, 1H), 3.41 -3.34 (m, 1H), 3.31 (s, 9H), 3.04-2.97 (m, 1H), 2.72 (s, 3H), 2.61 (s, 3H), 2.43-2.32 (m, 7H), 2.05-1.93 (m, 1H), 1.62 (d, J = 6.9 Hz, 4H). LCMS [M+1] ⁺ : 416.3. 12-70

3-(( R )-1-((7-((1 R ,4 R )-5-(2-methoxyethyl)-2,5-diazabicyclo[2.2.2]oct-2 -Yl)-4-methylpyrido[3,4- d ]

-1-yl)amino)ethyl)-2-methylbenzonitrile ¹ H NMR (400 MHz, CD ₃ OD) δ = 9.17-9.14 (m, 1H), 7.74 (dd, J = 7.8, 1.3 Hz, 1H), 7.54 (dd, J = 7.7, 1.3 Hz, 1H), 7.31-7.25 (m, 2H), 5.47 (q, J = 6.9 Hz, 1H), 5.09 (s, 1H), 4.09 (d, J = 12.4 Hz, 1H), 3.71 (d, J = 12.4 Hz, 1H ), 3.64 (t, J = 5.3 Hz, 2H), 3.57 (br s, 2H), 3.39 (s, 3H), 3.23-3.08 (m, 3H), 2.33 (d, J = 9.1 Hz, 1H), 2.03 (t, J = 8.3 Hz, 2H), 1.93-1.83 (m, 1H), 1.66 (d, J = 7.0 Hz, 3H). LCMS [M+1] ⁺ : 472.3. 12-71

( R )-2-methyl-3-(1-((4-methyl-7-(6-oxa-2-azaspiro[3.4]oct-2-yl)pyrido[3,4- d ]

-1-yl)amino)ethyl)benzonitrile hydrochloride ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 14.73 (s, 1H), 9.24 (d, J = 2.7 Hz, 1H), 8.88 (s, 1H), 7.80 (d, J = 8.2 Hz, 1H ), 7.66 (d, J = 7.6 Hz, 1H), 7.52 (s, 1H), 7.41-7.32 (m, 1H), 5.34-5.29 (m, 1H), 4.27 (s, 4H), 3.92-3.87 ( m, 2H), 3.83-3.74 (m, 2H), 2.74 (s, 3H), 2.66 (s, 3H), 2.29-2.21 (m, 2H), 1.60 (d, J = 7.1, 3H). LCMS [M+1] ⁺ : 415.2. 12-72

( R )-2-Methyl-3-(1-((4-methyl-7-(5-methyl-8-oxa-2,5-diazaspiro[3.5]non-2-yl )Pyrido[3,4-d]ta

-1-yl)amino)ethyl)benzonitrile formate ¹ H NMR (400 MHz, CD ₃ OD) δ 9.06 (s, 1H), 8.49 (s, 1H), 7.72 (dd, J = 7.9, 1.3 Hz, 1H), 7.51 (dd, J = 7.7, 1.3 Hz , 1H), 7.27 (t, J = 7.8 Hz, 1H), 7.15 (s, 1H), 5.50 (q, J = 6.9 Hz, 1H), 4.38 (d, J = 10.0 Hz, 2H), 3.89 (dd , J = 10.0, 2.9 Hz, 2H), 3.82-3.73 (m, 4H), 2.71 (s, 3H), 2.69 (s, 3H), 2.65-2.58 (m, 2H), 2.50 (s, 3H), 1.63 (d, J = 7.0 Hz, 3H). LCMS [M+1] ⁺ : 444.2. 12-73

3-(( R )-1-((7-(( R )-hexahydropyrrolo[1,2-a]pyridine

-2(1 H )-yl)-4-methylpyrido[3,4- d ]

-1-yl)amino)ethyl)-2-methylbenzonitrile ¹ H NMR (400 MHz, methanol- d ₄ ) δ 8.99 (d, J = 0.9 Hz, 1H), 7.70 (dd, J = 7.9, 1.4 Hz, 1H), 7.49 (dd, J = 7.7, 1.4 Hz, 1H), 7.34 (d, J = 1.0 Hz, 1H), 7.24 (t, J = 7.8 Hz, 1H), 5.57 (q, J = 6.9 Hz, 1H), 4.71 (d, J = 12.4 Hz, 1H) , 4.62 (d, J = 13.4 Hz, 1H), 3.24-3.07 (m, 3H), 2.85-2.72 (m, 2H), 2.72 (s, 3H), 2.61 (s, 3H), 2.41-2.13 (m , 3H), 2.06-1.91 (m, 1H), 1.94-1.83.(m, 1H), 1.61 (d, J = 6.9 Hz, 3H), 1.61-1.48 (m, 1H). LCMS [M+1] ⁺ : 428.2. 12-74

N -(( R )-1-(2-chloro-3-fluorophenyl)ethyl)-7-(( S )-hexahydropyridine

And [2,1- c ][1,4]

-8(1 H )-yl)-4-methylpyrido[3,4- d ]

-1-carbamate ¹ H NMR (400 MHz, CD ₃ OD) δ = 9.13 (s, 1H), 8.45 (s, 1H), 7.47 (s, 1H), 7.30-7.23 (m, 1H), 7.26-7.16 (m, 1H) ), 7.13-7.04 (m, 1H), 5.62 (q, J = 7.0 Hz, 1H), 4.72 (d, J = 13.3 Hz, 1H), 4.54-4.47 (m, 1H), 3.92-3.80 (m, 2H), 3.79-3.68 (m, 1H), 3.37 (t, J = 10.6 Hz, 1H), 3.31-3.20 (m, 1H), 3.02-2.93 (m, 1H), 2.83-2.72 (m, 2H) , 2.70 (s, 3H), 2.46-2.35 (m, 2H), 2.39-2.28 (m, 1H), 1.65 (d, J = 7.0 Hz, 3H). LCMS [M+1] ⁺ : 457.2. 12-75

N -(( R )-1-(2,3-difluorophenyl)ethyl)-7-(( S )-hexahydropyridine

And [2,1- c ][1,4]

-8(1 H )-yl)-4-methylpyrido[3,4- d ]

-1-carbamate ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 8.99 (s, 1H), 7.47 (d, J = 7.1 Hz, 1H), 7.41 (s, 1H), 7.30-7.15 (m, 2H), 7.14 -7.04 (m, 1H), 5.67-5.59 (m, 1H), 4.44 (d, J = 12.5 Hz, 1H), 4.37 (d, J = 12.4 Hz, 1H), 3.86-3.76 (m, 2H), 3.63-3.52 (m, 1H), 3.29-3.19 (m, 1H), 3.14-3.02 (m, 1H), 2.92 (d, J = 11.5 Hz, 1H), 2.73 (d, J = 11.3 Hz, 1H) , 2.64-2.57 (m, 1H), 2.56 (s, 3H), 2.36-2.18 (m, 3H), 1.60 (d, J = 7.0 Hz, 3H). LCMS [M+1] ⁺ : 441.1. 12-76

2-Methyl-3-(( R )-1-((4-methyl-7-((1 R ,4 R )-5-(2,2,2-trifluoroethyl)-2,5 -Diazabicyclo[2.2.2]oct-2-yl)pyrido[3,4- d ]ta

-1-yl)amino)ethyl)benzonitrile ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 8.93 (s, 1H), 7.72 (d, J = 8.0 Hz, 1H), 7.61 (d, J = 7.5 Hz, 1H), 7.47 (d, J = 6.8 Hz, 1H), 7.31 (t, J = 7.8 Hz, 1H), 7.08 (s, 1H), 5.57-5.46 (m, 1H), 3.78 (d, J = 11.2 Hz, 1H), 3.56-3.44 (m, 1H), 3.24-3.07 (m, 4H), 2.65 (s, 3H), 2.52 (s, 3H), 2.13-1.97 (m, 1H), 1.93-1.78 (m, 2H), 1.76-1.67 (m, 2H), 1.54 (d, J = 6.9 Hz, 3H). LCMS [M+1] ⁺ : 496.0. 12-77

7-(6-oxa-3-azabicyclo[3.1.1]heptan-3-yl) -N -(( R )-1-(2-chloro-3-fluorophenyl)ethyl)-4 -Methylpyrido[3,4- d ]ta

-1-carbamate ¹ H NMR (400 MHz, CD ₃ OD) δ = 9.17 (s, 1H), 8.51 (s, 1H), 7.35 (s, 1H), 7.33-7.27 (m, 1H), 7.27-7.17 (m, 1H) ), 7.14-7.05 (m, 1H), 5.68 (q, J = 6.9 Hz, 1H), 4.87 (s, 2H), 4.02 (d, J = 13.0 Hz, 2H), 3.88 (d, J = 12.8 Hz , 2H), 3.42-3.34 (m, 1H), 2.72 (s, 3H), 2.07-2.00 (m, 1H), 1.68 (d, J = 7.0 Hz, 3H). LCMS [M+1] ⁺ : 414.2. 12-78

( R )-2-methyl-3-(1-((4-methyl-7-(6-(2,2,2-trifluoroethyl)-2,6-diazaspiro[3.4] Oct-2-yl)pyrido[3,4- d ]

-1-yl)amino)ethyl)benzonitrile formate ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 8.97 (s, 1H), 7.71 (d, J = 8.0 Hz, 1H), 7.61 (d, J = 7.7 Hz, 1H), 7.58-7.52 (m , 1H), 7.32 (t, J = 7.8 Hz, 1H), 7.08 (s, 1H), 5.48 (q, J = 6.9 Hz, 1H), 4.11-4.01 (m, 4H), 3.32-3.25 (m, 2H), 3.00 (s, 2H), 2.80 (t, J = 7.1 Hz, 2H), 2.64 (s, 3H), 2.55 (s, 3H), 2.13 (t, J = 7.0 Hz, 2H), 1.53 ( d, J = 6.9 Hz, 3H). LCMS [M+1] ⁺ : 496.4. 12-79

N -(( R )-1-(4-fluoro-2-methylphenyl)ethyl)-7-(( S )-hexahydropyridine

And [2,1- c ][1,4]

-8(1 H )-yl)-4-methylpyrido[3,4- d ]

-1-amine ¹ H NMR (400 MHz, CD ₃ OD) δ = 9.25 (s, 1H), 7.59 (s, 1H), 7.43 (dd, J = 8.6, 5.8 Hz, 1H), 6.95-6.84 (m, 2H), 5.40 (q, J = 7.0 Hz, 1H), 3.98-3.69 (m, 3H), 3.51-3.37 (m, 4H), 3.22-2.86 (m, 3H), 2.81 (s, 3H), 2.68-2.53 ( m, 3H), 2.50 (s, 3H), 1.65 (d, J = 6.9 Hz, 3H). LCMS [M+1] ⁺ : 437.3. 12-80

( R )-1-(1-((1-(2-chloro-3-fluorophenyl)ethyl)amino)-4-methylpyrido[3,4- d ]

-7-yl)-3-methylazetidine-3-ol formate ¹ H NMR (400 MHz, CD ₃ OD) δ = 9.06 (d, J = 0.8 Hz, 1H), 8.48 (s, 1H), 7.29-7.16 (m, 2H), 7.15-7.10 (m, 1H), 7.13-7.04 (m, 1H), 5.63 (q, J = 6.9 Hz, 1H), 4.21-4.14 (m, 2H), 4.14-4.08 (m, 2H), 2.68 (s, 3H), 1.65 (d, J = 7.0 Hz, 3H), 1.60 (s, 3H). LCMS [M+1] ⁺ : 402.2. 12-81

( R )-1-(1-((1-(3-Fluoro-2-methylphenyl)ethyl)amino)-4-methylpyrido[3,4- d ]

-7-yl)-3-methylazetidine-3-ol ¹ H NMR (400 MHz, CD ₃ OD) δ = 8.94-8.89 (m, 1H), 7.22 (d, J = 7.7 Hz, 1H), 7.13-7.00 (m, 2H), 6.86 (t, J = 8.9 Hz, 1H), 5.58 (q, J = 6.9 Hz, 1H), 4.13-4.07 (m, 2H), 4.07-4.01 (m, 2H), 2.62 (s, 3H), 2.37 (s, 3H), 1.62 -1.56 (m, 6H). LCMS [M+1] ⁺ : 382.3. 12-82

( R )-7-(3-(dimethylamino)-3-methylazetidin-1-yl) -N -(1-(3-fluoro-2-methylphenyl)ethyl Yl)-4-methylpyrido[3,4- d ]

-1-amine dihydrochloride ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 14.91 (s, 1H), 12.41 (s, 1H), 9.12 (s, 1H), 8.90 (s, 1H), 7.67 (s, 1H), 7.22 (d, J = 7.8 Hz, 1H), 7.08-6.98 (m, 1H), 6.86 (t, J = 9.0 Hz, 1H), 5.23-5.11 (m, 1H), 4.54-4.46 (m, 2H), 4.06-4.01 (m, 2H), 2.64 (s, 3H), 2.57 (s, 6H), 2.20 (s, 3H), 1.56 (s, 3H), 1.47 (d, J = 6.9 Hz, 3H). LCMS [M+1] ⁺ : 409.2. 12-83

( R ) -N -(1-(2,3-Difluorophenyl)ethyl)-7-(3-(dimethylamino)-3-methylazetidin-1-yl) -4-methylpyrido[3,4- d ]

-1-carbamate ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 8.97 (s, 1H), 8.14 (s, 1H), 7.45 (s, 1H), 7.30-7.16 (m, 2H), 7.13-7.06 (m, 2H), 5.63-5.59 (m, 1H), 3.91 (dd, J = 8.2, 4.3 Hz, 2H), 3.85-3.78 (m, 2H), 2.56 (s, 3H), 2.16 (s, 6H), 1.60 (d, J = 7.0 Hz, 3H), 1.33 (s, 3H). LCMS [M+1] ⁺ : 413.1. 12-84

7-(6-oxa-3-azabicyclo[3.1.1]heptan-3-yl) -N -(( R )-1-(4-fluoro-2-methylphenyl)ethyl)- 4-methylpyrido[3,4- d ]

-1-amine ¹ H NMR (400 MHz, CD ₃ OD) δ 9.19 (s, 1H), 7.44 (dd, J = 8.6, 5.9 Hz, 1H), 7.34 (s, 1H), 6.93-6.80 (m, 2H), 5.48 (q, J = 6.9 Hz, 1H), 4.85 (s, 2H), 4.02 (d, J = 13.0 Hz, 2H), 3.88 (d, J = 12.9 Hz, 2H), 3.41-3.33 (m, 1H) , 2.76 (s, 3H), 2.49 (s, 3H), 2.02 (d, J = 9.1 Hz, 1H), 1.64 (d, J = 6.9 Hz, 3H). LCMS [M+1] ⁺ : 394.3. 12-85

( R ) -N -(1-(2-chloro-3-fluorophenyl)ethyl)-7-(3-(dimethylamino)-3-methylazetidin-1-yl )-4-methylpyrido[3,4- d ]

-1-carbamate ¹ H NMR (400 MHz, CD ₃ OD) δ = 9.03 (d, J = 0.8 Hz, 1H), 7.30-7.23 (m, 1H), 7.25-7.15 (m, 1H), 7.12 (s, 1H), 7.12-7.03 (m, 1H), 5.65 (q, J = 7.0 Hz, 1H), 4.09 (d, J = 8.9 Hz, 2H), 3.95 (d, J = 8.8 Hz, 2H), 2.66 (s, 3H ), 2.30 (s, 6H), 1.65 (d, J = 6.9 Hz, 3H), 1.47 (s, 3H). LCMS [M+1] ⁺ : 429.2. 12-86

2-Methyl-3-(( R )-1-((4-methyl-7-(( R )-octahydro-2 H -pyrido[1,2- a ]pyridine

-2-yl)pyrido[3,4- d ]

-1-yl)amino)ethyl)benzonitrile formate ¹ H NMR (400 MHz, CD ₃ OD) δ = 9.09 (s, 1H), 7.72 (d, J = 8.0 Hz, 1H), 7.53 (d, J = 7.7 Hz, 1H), 7.41 (s, 1H) , 7.28 (t, J = 7.8 Hz, 1H), 5.54 (q, J = 7.0 Hz, 1H), 4.70 (d, J = 13.2 Hz, 1H), 4.51 (d, J = 13.2 Hz, 1H), 3.28 -3.16 (m, 1H), 3.04-2.96 (m, 2H), 2.84 (dd, J = 13.2, 10.7 Hz, 1H), 2.74 (s, 3H), 2.69 (s, 3H), 2.41 (td, J = 12.0, 3.3 Hz, 1H), 2.27-2.13 (m, 2H), 1.92-1.85 (m, 1H), 1.83-1.69 (m, 3H), 1.64 (d, J = 7.0 Hz, 3H), 1.50- 1.33 (m, 2H). LCMS [M+1] ⁺ : 442.3. 12-87

( R )-2-methyl-3-(1-((4-methyl-7-(3-methyl-3-

Alkylazetidin-1-yl)pyrido[3,4- d ]

-1-yl)amino)ethyl)benzonitrile formate ¹ H NMR (400 MHz, CD ₃ OD) δ = 9.04 (d, J = 0.9 Hz, 1H), 8.51 (s, 1H), 7.72 (dd, J = 7.9, 1.4 Hz, 1H), 7.52 (dd, J = 7.7, 1.4 Hz, 1H), 7.28 (t, J = 7.8 Hz, 1H), 7.08 (s, 1H), 5.52 (q, J = 6.9 Hz, 1H), 4.12-4.04 (m, 2H), 3.95-3.87 (m, 2H), 3.78-3.71 (m, 4H), 2.72 (s, 3H), 2.68 (s, 3H), 2.61-2.49 (m, 4H), 1.63 (d, J = 7.0 Hz, 3H), 1.47 (s, 3H). LCMS [M+1] ⁺ : 458.3. 12-88

( R )-2-Methyl-3-(1-((4-methyl-7-(5-methyl-2,5-diazaspiro[3.4]oct-2-yl)pyrido[3 ,4- d ]

-1-yl)amino)ethyl)benzonitrile ¹ H NMR (400 MHz, CD ₃ OD) δ = 8.95 (d, J = 0.9 Hz, 1H), 7.72 (dd, J = 7.9, 1.4 Hz, 1H), 7.50 (dd, J = 7.7, 1.3 Hz, 1H), 7.26 (t, J = 7.8 Hz, 1H), 7.05 (d, J = 0.9 Hz, 1H), 5.58 (q, J = 6.9 Hz, 1H), 4.34 (dd, J = 9.2, 3.3 Hz, 2H), 3.99 (d, J = 9.2 Hz, 2H), 2.82 (t, J = 7.3 Hz, 2H), 2.73 (s, 3H), 2.62 (s, 3H), 2.51 (s, 3H), 2.26- 2.18 (m, 2H), 1.94-1.82 (m, 2H), 1.62 (d, J = 6.9 Hz, 3H). LCMS [M+1] ⁺ : 428.2. 12-89

3-(( R )-1-((7-((1 R ,4 R )-5-(2-hydroxyethyl)-2,5-diazabicyclo[2.2.2]oct-2-yl )-4-methylpyrido[3,4- d ]

-1-yl)amino)ethyl)-2-methylbenzonitrile ¹ H NMR (400 MHz, CD ₃ OD) δ 9.19 (s, 1H), 7.76 (dd, J = 7.9, 1.4 Hz, 1H), 7.54 (dd, J = 7.8, 1.3 Hz, 1H), 7.35 (s , 1H), 7.29 (t, J = 7.8 Hz, 1H), 5.47 (q, J = 6.9 Hz, 1H), 5.15 (s, 1H), 4.14 (dt, J = 12.8, 2.7 Hz, 1H), 3.85 -3.68 (m, 4H), 3.45-3.41 (m, 2H), 3.27-3.12 (m, 2H), 2.76 (s, 3H), 2.73 (s, 3H), 2.39-2.34 (m, 1H), 2.11 -2.02 (m, 2H), 2.00-1.88 (m, 1H), 1.67 (d, J = 7.0 Hz, 3H). LCMS [M+1] ⁺ : 458.2. 12-90

( R )-3-(1-((7-(4-(2-methoxyethyl)piper

-1-yl)-4-methylpyrido[3,4- d ]

-1-yl)amino)ethyl)-2-methylbenzonitrile ¹ H NMR (400 MHz, CD ₃ OD) δ = 8.97 (d, J = 0.8 Hz, 1H), 7.72 (dd, J = 8.0, 1.4 Hz, 1H), 7.48 (dd, J = 7.7, 1.4 Hz, 1H), 7.30 (d, J = 0.9 Hz, 1H), 7.24 (t, J = 7.8 Hz, 1H), 5.57 (q, J = 6.9 Hz, 1H), 3.84-3.77 (m, 4H), 3.60 ( t, J = 5.5 Hz, 2H), 3.38 (s, 3H), 2.71 (s, 3H), 2.69-2.64 (m, 6H), 2.61 (s, 3H), 1.61 (d, J = 7.0 Hz, 3H ). LCMS [M+1] ⁺ : 446.2. 12-91

( R )-2-Methyl-3-(1-((4-methyl-7-(6-methyl-2,6-diazaspiro[3.3]heptan-2-yl)pyrido[3 ,4- d ]

-1-yl)amino)ethyl)benzonitrile formate ¹ H NMR (400 MHz, CD ₃ OD) δ = 9.11 (s, 1H), 7.73 (d, J = 7.8 Hz, 1H), 7.54 (dd, J = 7.7, 1.3 Hz, 1H), 7.29 (t, J = 7.8 Hz, 1H), 7.20 (s, 1H), 5.47 (q, J = 6.8 Hz, 1H), 4.50 (s, 4H), 4.36 (s, 4H), 2.90 (s, 3H), 2.73 ( s, 6H), 1.66 (d, J = 7.0 Hz, 3H). LCMS [M+1] ⁺ : 414.1. 12-92

( R ) -N -(1-(2-Fluoro-3-(trifluoromethyl)phenyl)ethyl)-4-methyl-7-(6-methyl-2,6-diazepine [3.3]Hept-2-yl)pyrido[3,4- d ]

-1-amine ¹ H NMR (400 MHz, CD ₃ OD) δ 8.95 (s, 1H), 7.71-7.62 (m, 1H), 7.57-7.48 (m, 1H), 7.26-7.18 (m, 1H), 7.05 (s, 1H), 5.69 (q, J = 7.0 Hz, 1H), 4.29 (s, 4H), 3.54 (s, 4H), 2.61 (s, 3H), 2.39 (s, 3H), 1.69 (d, J = 7.0 Hz, 3H). LCMS [M+1] ⁺ : 461.6. 12-93

( R )-3-(1-((7-(4-(2-hydroxyethyl)piper

-1-yl)-4-methylpyrido[3,4- d ]

-1-yl)amino)ethyl)-2-methylbenzonitrile ¹ H NMR (400 MHz, CD ₃ OD) δ = 8.98 (s, 1H), 7.72 (dd, J = 7.9, 1.3 Hz, 1H), 7.49 (dd, J = 7.7, 1.3 Hz, 1H), 7.31 ( s, 1H), 7.25 (t, J = 7.8 Hz, 1H), 5.58 (q, J = 6.9 Hz, 1H), 3.86-3.79 (m, 4H), 3.76 (t, J = 5.9 Hz, 2H), 2.72 (s, 3H), 2.71-2.60 (m, 9H), 1.61 (d, J = 7.0 Hz, 3H). LCMS [M+1] ⁺ : 432.2. 12-94

( R )-3-(1-((7-(4-(cyclopropanecarbonyl)piper

-1-yl)-4-methylpyrido[3,4- d ]

-1-yl)amino)ethyl)-2-methylbenzonitrile formate ¹ H NMR (400 MHz, CD ₃ OD) δ = 9.12 (s, 1H), 7.74 (dd, J = 8.0, 1.4 Hz, 1H), 7.53 (dd, J = 7.7, 1.4 Hz, 1H), 7.44 ( s, 1H), 7.28 (t, J = 7.8 Hz, 1H), 5.54 (q, J = 6.9 Hz, 1H), 4.01 (d, J = 15.7 Hz, 4H), 3.84 (d, J = 24.5 Hz, 4H), 2.73 (s, 3H), 2.70 (s, 3H), 2.11-2.00 (m, 1H), 1.65 (d, J = 6.9 Hz, 3H), 1.00-0.91 (m, 2H), 0.94-0.85 (m, 2H). LCMS [M+1] ⁺ : 456.2. 12-95

( R )-3-(1-((7-(4-acetoxypiper

-1-yl)-4-methylpyrido[3,4- d ]

-1-yl)amino)ethyl)-2-methylbenzonitrile formate ¹ H NMR (400 MHz, CD ₃ OD) δ = 9.10 (d, J = 0.8 Hz, 1H), 7.71 (dd, J = 8.0, 1.4 Hz, 1H), 7.51 (dd, J = 7.6, 1.3 Hz, 1H), 7.42 (s, 1H), 7.26 (t, J = 7.8 Hz, 1H), 5.50 (q, J = 7.0 Hz, 1H), 4.01-3.94 (m, 2H), 3.90-3.81 (m, 2H ), 3.81-3.69 (m, 4H), 2.71 (s, 3H), 2.68 (s, 3H), 2.18 (s, 3H), 1.63 (d, J = 6.9 Hz, 3H). LCMS [M+1] ⁺ : 430.1. 12-96

3-(( R )-1-((7-(( R )-3-(dimethylamino)pyrrolidin-1-yl)-4-methylpyrido[3,4- d ]

-1-yl)amino)ethyl)-2-methylbenzonitrile ¹ H NMR (400 MHz, CD ₃ OD) δ = 8.96 (d, J = 0.8 Hz, 1H), 7.73 (dd, J = 8.0, 1.3 Hz, 1H), 7.50 (dd, J = 7.5, 1.3 Hz, 1H), 7.25 (t, J = 7.8 Hz, 1H), 7.03 (s, 1H), 5.59 (q, J = 6.9 Hz, 1H), 3.94-3.84 (m, 2H), 3.63-3.51 (m, 1H ), 3.41-3.34 (m, 1H), 3.06-2.96 (m, 1H), 2.73 (s, 3H), 2.62 (s, 3H), 2.39 (s, 7H), 2.07-1.91 (m, 1H), 1.63 (d, J = 6.9 Hz, 3H). LCMS [M+1] ⁺ : 416.2. 12-97

7-(( S )-3-(dimethylamino)pyrrolidin-1-yl) -N -(( R )-1-(2-fluoro-3-(trifluoromethyl)phenyl)ethyl Yl)-4-methylpyrido[3,4- d ]

-1-carbamate ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 8.97 (s, 1H), 7.70 (t, J = 7.2 Hz, 1H), 7.61 (t, J = 7.2 Hz, 1H), 7.47 (d, J = 6.6 Hz, 1H), 7.30 (t, J = 7.8 Hz, 1H), 7.07 (s, 1H), 5.68-5.61 (m, 1H), 3.87-3.79 (m, 1H), 3.79-3.72 (m, 1H), 3.56-3.44 (m, 1H), 3.34-3.25 (m, 1H), 2.95-2.86 (m, 1H), 2.54 (s, 3H), 2.26 (s, 7H), 1.98-1.83 (m, 1H), 1.61 (d, J = 7.0 Hz, 3H). LCMS [M+1] ⁺ : 463.2. 12-98

7-(6-oxa-3-azabicyclo[3.1.1]heptan-3-yl) -N -(( R )-1-(2,3-difluorophenyl)ethyl)-4- Pico[3,4- d]

-1-amine ¹ H NMR (400 MHz, CD ₃ OD) δ = 9.08 (s, 1H), 7.24 (s, 1H), 7.20 (t, J = 7.0 Hz, 1H), 7.12-6.99 (m, 2H), 5.70 ( q, J = 7.0 Hz, 1H), 3.99 (d, J = 12.7 Hz, 2H), 3.84 (d, J = 12.5 Hz, 2H), 3.41-3.34 (m, 2H), 2.66 (s, 3H), 2.08-2.01 (m, 1H), 1.70 (d, J = 7.0 Hz, 3H). LCMS [M+1] ⁺ : 398.0. 12-99

7-((1 R ,4 R )-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)- N -(( R )-1-(3-(difluoromethyl )-2-fluorophenyl)ethyl)-4-methylpyrido[3,4- d ]

-1-amine ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 8.97 (s, 1H), 7.56 (t, J = 7.3 Hz, 1H), 7.43 (dt, J = 28.4, 8.1 Hz, 2H), 7.27-7.09 (m, 3H), 5.70-5.58 (m, 1H), 5.08 (s, 1H), 4.78 (s, 1H), 3.92-3.85 (m, 1H), 3.74-3.68 (m, 1H), 3.66-3.59 (m, 1H), 3.44-3.36 (m, 1H), 3.31-3.28 (m, 1H), 2.54 (s, 3H), 2.03-1.93 (m, 2H), 1.60 (d, J = 7.0 Hz, 3H ). LCMS [M+1] ⁺ : 430.1. 12-100

N -(( R )-1-(3-(Difluoromethyl)-2-fluorophenyl)ethyl)-7-(( S )-hexahydropyridine

And [2,1- c ][1,4]

-8(1 H )-yl)-4-methylpyrido[3,4-d]

-1-amine ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.99 (s, 1H), 7.56 (t, J = 7.5 Hz, 2H), 7.50-7.08 (m, 4H), 5.70-5.59 (m, 1H), 4.49-4.34 (m, 2H), 3.86-3.76 (m, 2H), 3.63-3.55 (m, 1H), 3.27-3.22 (m, 1H), 3.11-3.06 (m, 1H), 2.96-2.89 (m , 1H), 2.77-2.69 (m, 1H), 2.64-2.57 (m, 1H), 2.55 (s, 3H), 2.35-2.17 (m, 3H), 1.60 (d, J = 7.0 Hz, 3H). LCMS [M+1] ⁺ : 473.3. 12-101

( R )-1-(1-((1-(3-(Difluoromethyl)-2-fluorophenyl)ethyl)amino)-4-methylpyrido[3,4- d ]

-7-yl)-3-methylazetidine-3-ol ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.96 (s, 1H), 7.57 (t, J = 7.5 Hz, 1H), 7.51-7.41 (m, 2H), 7.28-7.20 (m, 1H), 7.13-7.07 (m, 1H), 5.73 (s, 1H), 5.70-5.59 (m, 1H), 4.06-3.93 (m, 4H), 2.55 (s, 3H), 1.60 (d, J = 7.0 Hz, 3H), 1.50 (s, 3H). LCMS [M+1] ⁺ : 418.0. 12-102

( R ) -N -(1-(3-(Difluoromethyl)-2-fluorophenyl)ethyl)-7-(4-ethylpiper

-1-yl)-4-methylpyrido[3,4- d ]

-1-amine ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 9.00 (s, 1H), 7.60-7.10 (m, 5H), 5.70-5.60 (m, 1H), 3.74 (t, J = 5.1 Hz, 4H) , 2.57-2.53 (m, 7H), 2.42 (q, J = 7.2 Hz, 2H), 1.61 (d, J = 7.0 Hz, 3H), 1.08 (t, J = 7.1 Hz, 3H). LCMS [M+1] ⁺ : 445.7. 12-103

5-Fluoro-3-(( R )-1-((7-(( S )-hexahydropyridine

And [2,1- c ][1,4]

-8(1 H )-yl)-4-methylpyrido[3,4- d ]

-1-yl)amino)ethyl)-2-methylbenzonitrile formate ¹ H NMR (400 MHz, CD ₃ OD) δ = 9.18 (s, 1H), 8.33 (s, 1H), 7.50-7.43 (m, 2H), 7.35 (dd, J = 7.9, 2.8 Hz, 1H), 5.46-5.36 (m, 1H), 4.74 (d, J = 13.5 Hz, 1H), 4.54 (d, J = 13.0 Hz, 1H), 3.93-3.82 (m, 2H), 3.79-3.68 (m, 1H) , 3.43-3.33 (m, 1H), 3.31-3.23 (m, 1H), 3.03-2.95 (m, 1H), 2.87-2.77 (m, 2H), 2.75 (s, 3H), 2.70 (s, 3H) , 2.47-2.29 (m, 3H), 1.63 (d, J = 7.0 Hz, 3H). LCMS [M+1] ⁺ : 462.2. 12-104

( R )-3-(1-((7-(4-(dimethylamino)-4-methylpiperidin-1-yl)-4-methylpyrido[3,4- d ]

-1-yl)amino)ethyl)-5-fluoro-2-methylbenzonitrile ¹ H NMR (400 MHz, CD ₃ OD) δ = 9.00 (d, J = 0.8 Hz, 1H), 7.47 (dd, J = 9.9, 2.8 Hz, 1H), 7.34-7.27 (m, 2H), 5.59- 5.49 (m, 1H), 4.28-4.20 (m, 2H), 3.50-3.39 (m, 2H), 2.70 (s, 3H), 2.63 (s, 3H), 2.29 (s, 6H), 1.79-1.75 ( m, 4H), 1.61 (d, J = 7.0 Hz, 3H), 1.13 (s, 3H). LCMS [M+1] ⁺ : 462.4. 12-105

3-(( R )-1-((7-((1 R ,4 R )-2-oxa-5-azabicyclo[2.2.1]hept-5-yl)-4-methylpyrido [3,4- d ]

-1-yl)amino)ethyl)-5-fluoro-2-methylbenzonitrile ¹ H NMR (400 MHz, CD ₃ OD) δ 8.98 (s, 1H), 7.46 (dd, J = 10.0, 2.8 Hz, 1H), 7.30 (dd, J = 7.9, 2.8 Hz, 1H), 7.07 (s , 1H), 5.58-5.48 (m, 1H), 5.17 (s, 1H), 4.81 (s, 1H), 4.00-3.93 (m, 1H), 3.87 (d, J = 7.4 Hz, 1H), 3.72- 3.64 (m, 1H), 3.51 (d, J = 10.3 Hz, 1H), 2.70 (s, 3H), 2.64 (s, 3H), 2.10-2.05 (m, 2H), 1.61 (d, J = 7.0 Hz , 3H). LCMS [M+1] ⁺ : 419.3. 12-106

3-((1 R )-1-((7-(6-oxa-3-azabicyclo[3.1.1]hept-3-yl)-4-methylpyrido[3,4- d ] despair

-1-yl)amino)ethyl)-5-fluoro-2-methylbenzonitrile formate ¹ H NMR (400 MHz, CD ₃ OD) δ = 9.17 (s, 1H), 7.50 (dd, J = 9.9, 2.8 Hz, 1H), 7.32 (dd, J = 7.9, 2.8 Hz, 1H), 7.30 ( s, 1H), 5.53-5.43 (m, 1H), 4.88-4.82 (m, 2H), 4.03-3.95 (m, 2H), 3.90-3.82 (m, 2H), 3.41-3.32 (m, 1H), 2.74 (s, 3H), 2.69 (s, 3H), 2.02 (d, J = 9.1 Hz, 1H), 1.64 (d, J = 7.0 Hz, 3H). LCMS [M+1] ⁺ : 419.2. 12-107

( R )-5-fluoro-3-(1-((7-(3-hydroxy-3-methylazetidin-1-yl)-4-methylpyrido[3,4- d ] despair

-1-yl)amino)ethyl)-2-methylbenzonitrile ¹ H NMR (400 MHz, CD ₃ OD) δ = 9.02 (s, 1H), 7.47 (dd, J = 9.8, 2.8 Hz, 1H), 7.33 (dd, J = 7.9, 2.9 Hz, 1H), 7.06 ( s, 1H), 5.47 (q, J = 7.0 Hz, 1H), 4.19-4.06 (m, 4H), 2.69 (s, 3H), 2.68 (s, 3H), 1.63 (s, 3H), 1.61 (d , J = 1.7 Hz, 3H). LCMS [M+1] ⁺ : 407.2. 12-108

( R )-3-(1-((7-(3-(dimethylamino)-3-methylazetidin-1-yl)-4-methylpyrido[3,4- d ]

-1-yl)amino)ethyl)-5-fluoro-2-methylbenzonitrile ¹ H NMR (400 MHz, CD ₃ OD) δ 8.95 (s, 1H), 7.47 (dd, J = 9.9, 2.8 Hz, 1H), 7.29 (dd, J = 7.9, 2.8 Hz, 1H), 7.02 (s , 1H), 5.58-5.48 (m, 1H), 4.06-3.98 (m, 2H), 3.93-3.84 (m, 2H), 2.68 (s, 3H), 2.64 (s, 3H), 2.27 (s, 6H) ), 1.60 (d, J = 7.0 Hz, 3H), 1.45 (s, 3H). LCMS [M+1] ⁺ : 434.2. 12-109

7-((1 R ,4 R )-2-oxa-5-azabicyclo[2.2.1]hept-5-yl)- N -(( R )-1-(5-fluoro-2-methyl 3-(trifluoromethyl)phenyl)ethyl)-4-methylpyrido[3,4- d ]

-1-amine ¹ H NMR (400 MHz, CD ₃ OD) δ = 9.00 (s, 1H), 7.43 (dd, J = 9.9, 2.8 Hz, 1H), 7.25 (dd, J = 8.8, 2.8 Hz, 1H), 7.10 ( s, 1H), 5.69-5.59 (m, 1H), 5.18 (s, 1H), 4.82 (s, 1H), 4.01-3.94 (m, 1H), 3.91-3.85 (m, 1H), 3.74-3.66 ( m, 1H), 3.56-3.49 (m, 1H), 2.64 (s, 3H), 2.60 (s, 3H), 2.11-2.06 (m, 2H), 1.62 (d, J = 6.9 Hz, 3H). LCMS [M+1] ⁺ : 462.0. 12-110

( R )-7-(3-(dimethylamino)-3-methylazetidin-1-yl) -N -(1-(5-fluoro-2-methyl-3-( (Trifluoromethyl)phenyl)ethyl)-4-methylpyrido[3,4- d ]

-1-amine ¹ H NMR (400 MHz, CD ₃ OD) δ = 8.98 (s, 1H), 7.43 (dd, J = 9.8, 2.8 Hz, 1H), 7.26 (dd, J = 8.9, 2.8 Hz, 1H), 7.06 ( s, 1H), 5.68-5.60 (m, 1H), 4.10-4.02 (m, 2H), 3.97-3.89 (m, 2H), 2.64 (s, 3H), 2.59 (s, 3H), 2.29 (s, 6H), 1.62 (d, J = 7.0 Hz, 3H), 1.47 (s, 3H). LCMS [M+1] ⁺ : 477.0. 12-111

( R )-1-(1-((1-(5-Fluoro-2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-4-methylpyrido(3, 4- d ]

-7-yl)-3-methylazetidine-3-ol ¹ H NMR (400 MHz, CD ₃ OD) δ = 8.96 (s, 1H), 7.43 (dd, J = 9.9, 2.8 Hz, 1H), 7.26 (dd, J = 8.9, 2.8 Hz, 1H), 7.04 ( s, 1H), 5.64 (q, J = 6.9 Hz, 1H), 4.14 (dd, J = 8.8, 3.4 Hz, 2H), 4.08 (dd, J = 8.8, 3.7 Hz, 2H), 2.63 (s, 3H ), 2.60 (s, 3H), 1.65-1.59 (m, 6H). LCMS [M+1] ⁺ : 450.4. 12-112

N -(( R )-1-(5-fluoro-2-methyl-3-(trifluoromethyl)phenyl)ethyl)-7-(( S )-hexahydropyridine

And [2,1- c ][1,4]

-8(1 H )-yl)-4-methylpyrido[3,4- d ]

-1-amine ¹ H NMR (400 MHz, CD ₃ OD) δ = 9.04 (s, 1H), 7.46-7.39 (m, 1H), 7.36 (s, 1H), 7.29-7.22 (m, 1H), 5.69-5.61 (m , 1H), 4.68-4.57 (m, 1H), 4.48-4.40 (m, 1H), 3.94-3.85 (m, 2H), 3.81-3.70 (m, 1H), 3.45-3.35 (m, 1H), 3.25 -3.15 (m, 1H), 3.02-2.94 (m, 1H), 2.85-2.78 (m, 1H), 2.77-2.67 (m, 1H), 2.65 (s, 3H), 2.60 (s, 3H), 2.48 -2.32 (m, 3H), 1.62 (d, J = 6.9 Hz, 3H). LCMS [M+1] ⁺ : 505.5. 12-113

7-(6-oxa-3-azabicyclo[3.1.1]heptan-3-yl) -N -(( R )-1-(5-fluoro-2-methyl-3-(trifluoromethyl (Yl)phenyl)ethyl)-4-methylpyrido[3,4- d ]

-1-amine ¹ H NMR (400 MHz, CD ₃ OD) δ = 9.08 (s, 1H), 7.45 (d, J = 9.9 Hz, H), 7.27-7.17 (m, H), 5.70-5.63 (m, 1H), 4.03-3.96 (m, 3H), 3.88-3.80 (m, 2H), 3.39-3.34 (m, 2H), 2.67 (s, 2H), 2.61 (s, 3H), 2.05 (d, J = 8.9 Hz, 1H), 1.64 (d, J = 6.9 Hz, 2H). LCMS [M+1] ⁺ : 462.0. 12-114

3-(( R )-1-((7-((1 R ,4 R )-2-oxa-5-azabicyclo[2.2.1]hept-5-yl)-4-methylpyrido [3,4- d ]

-1-yl)amino)ethyl)-2,5-difluorobenzonitrile formate ¹ H NMR (400 MHz, CD ₃ OD) δ = 9.07 (s, 1H), 8.52 (s, 1H), 7.63-7.55 (m, 1H), 7.41-7.32 (m, 1H), 7.15 (s, 1H) ), 5.60-5.51 (m, 1H), 5.25-5.20 (m, 1H), 4.62-4.58 (m, 1H), 4.02-3.95 (m, 1H), 3.92-3.85 (m, 1H), 3.75-3.68 (m, 1H), 3.61-3.52 (m, 1H), 2.68 (s, 3H), 2.10 (s, 2H), 1.70 (d, J = 7.0 Hz, 3H). LCMS [M+1] ⁺ : 423.2. 12-115

( R ) -N -(1-(3-(Difluoromethyl)-2-fluorophenyl)ethyl)-7-(3-(dimethylamino)-3-methylazetidine Alk-1-yl)-4-methylpyrido[3,4- d ]

-1-amine ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.96 (s, 1H), 7.57 (t, J = 7.5 Hz, 1H), 7.51-7.36 (m, 2H), 7.28-7.20 (m, 2H), 7.11 (s, 1H), 5.70-5.58 (m, 1H), 3.91 (dd, J = 8.2, 4.8 Hz, 2H), 3.81 (dd, J = 8.2, 2.1 Hz, 2H), 2.55 (s, 3H) , 2.16 (s, 6H), 1.60 (d, J = 7.0 Hz, 3H), 1.33 (s, 3H). LCMS [M+1] ⁺ : 445.1. 12-116

( R ) -N -(1-(3-(Difluoromethyl)-2-fluorophenyl)ethyl)-4-methyl-7-(6-methyl-2,6-diazepine [3.3]Hept-2-yl)pyrido[3,4- d ]

-1-amine ¹ H NMR (400 MHz, CD ₃ OD) δ = 8.94 (s, 1H), 7.55 (t, J = 7.5 Hz, 1H), 7.44 (t, J = 7.1 Hz, 1H), 7.21-6.85 (m, 3H), 5.68 (q, J = 7.0 Hz, 1H), 4.28 (s, 4H), 3.53 (s, 4H), 2.62 (s, 3H), 2.38 (s, 3H), 1.69 (d, J = 7.0 Hz, 3H). LCMS [M+1] ⁺ : 443.5. 12-117

( R ) -N -(1-(3-(Difluoromethyl)-2-fluorophenyl)ethyl)-4-methyl-7-(4-methylpiper

-1-yl)pyrido[3,4- d ]

-1-amine ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 8.99 (s, 1H), 7.61-7.08 (m, 7H), 5.70-5.60 (m, 1H), 3.74 (t, J = 5.0 Hz, 4H) , 2.56 (s, 3H), 2.49-2.43 (m, 4H), 2.27 (s, 3H), 1.61 (d, J = 7.0 Hz, 3H). LCMS [M+1] ⁺ : 431.2. 12-118

( R )-7-(4-ethylpiper

-1-yl) -N -(1-(5-fluoro-2-methyl-3-(trifluoromethyl)phenyl)ethyl)-4-methylpyrido[3,4- d ]

-1-amine ¹ H NMR (400 MHz, CD ₃ OD) δ = 9.03 (s, 1H), 7.47-7.40 (m, 1H), 7.35 (s, 1H), 7.25 (dd, J = 8.8, 2.8 Hz, 1H), 5.64 (q, J = 6.9 Hz, 1H), 3.90-3.83 (m, 4H), 2.70-2.65 (m, 4H), 2.64 (s, 3H), 2.60 (s, 3H), 2.55 (q, J = 7.2 Hz, 2H), 1.62 (d, J = 6.9 Hz, 3H), 1.20 (t, J = 7.2 Hz, 3H). LCMS [M+1] ⁺ : 477.6. 12-119

( R ) -N -(1-(5-Fluoro-2-methyl-3-(trifluoromethyl)phenyl)ethyl)-4-methyl-7-(4-methylpiper

-1-yl)pyrido[3,4- d ]

-1-amine ¹ H NMR (400 MHz, CD ₃ OD) δ = 9.04 (s, 1H), 7.43 (dd, J = 9.8, 2.7 Hz, 1H), 7.36 (s, 1H), 7.25 (dd, J = 8.9, 2.8 Hz, 1H), 5.64 (q, J = 7.1 Hz, 1H), 3.90-3.83 (m, 4H), 2.67-2.58 (m, 10H), 2.40 (s, 3H), 1.62 (d, J = 6.9 Hz , 3H). LCMS [M+1] ⁺ : 463.4. 12-120

2,5-Difluoro-3-(( R )-1-((7-(( S )-hexahydropyridine

And [2,1- c ][1,4]

-8(1 H )-yl)-4-methylpyrido[3,4- d ]

-1-yl)amino)ethyl)benzonitrile ¹ H NMR (400 MHz, CD ₃ OD) δ = 9.20 (d, J = 0.8 Hz, 1H), 7.62 (dd, J = 9.3, 5.0 Hz, 1H), 7.50 (s, 1H), 7.41 (dd, J = 9.4, 5.7 Hz, 1H), 5.49 (q, J = 7.0 Hz, 1H), 4.77-4.72 (m, 2H), 4.57 (d, J = 13.4 Hz, 2H), 3.94-3.84 (m, 2H ), 3.75 (td, J = 11.5, 2.4 Hz, 1H), 3.45-3.35 (m, 1H), 3.01 (d, J = 11.5 Hz, 1H), 2.88-2.78 (m, 2H), 2.76 (s, 3H), 2.47-2.38 (m, 1H), 2.42-2.31 (m, 1H), 1.71 (d, J = 7.1 Hz, 3H). LCMS [M+1] ⁺ : 466.3. 12-121

3-((1 R )-1-((7-(6-oxa-3-azabicyclo[3.1.1]hept-3-yl)-4-methylpyrido[3,4- d ] despair

-1-yl)amino)ethyl)-2,5-difluorobenzonitrile ¹ H NMR (400 MHz, CD ₃ OD) δ 9.10 (s, 1H), 7.58 (dd, J = 9.2, 5.1 Hz, 1H), 7.37 (dd, J = 9.5, 5.7 Hz, 1H), 7.24 (s , 1H), 5.62 (q, J = 7.1 Hz, 1H), 4.89 (s, 1H), 4.00 (d, J = 12.8 Hz, 2H), 3.86 (d, J = 12.6 Hz, 2H), 3.42-3.34 (m, 2H), 2.68 (s, 3H), 2.06 (d, J = 9.0 Hz, 1H), 1.71 (d, J = 7.0 Hz, 3H). LCMS [M+1] ⁺ : 423.1. 12-122

( R )-3-(1-((7-(3-(dimethylamino)-3-methylazetidin-1-yl)-4-methylpyrido[3,4- d ]

-1-yl)amino)ethyl)-2,5-difluorobenzonitrile formate ¹ H NMR (400 MHz, CD ₃ OD) δ = 9.09 (d, J = 0.8 Hz, 1H), 8.45 (s, 1H), 7.60 (dd, J = 9.3, 5.1 Hz, 1H), 7.38 (dd, J = 9.5, 5.7 Hz, 1H), 7.12 (s, 1H), 5.52 (q, J = 7.0 Hz, 1H), 4.16-4.09 (m, 2H), 4.02-3.95 (m, 2H), 2.71 (s , 3H), 2.34 (s, 6H), 1.70 (d, J = 7.0 Hz, 3H), 1.49 (s, 3H). LCMS [M+1] ⁺ : 438.2. 12-123

( R )-3-(1-((7-(4-(dimethylamino)-4-methylpiperidin-1-yl)-4-methylpyrido[3,4- d ]

-1-yl)amino)ethyl)-2,5-difluorobenzonitrile formate ¹ H NMR (400 MHz, CD ₃ OD) δ = 9.07 (s, 1H), 8.51 (s, 1H), 7.59 (dd, J = 9.2, 5.1 Hz, 1H), 7.41 (s, 1H), 7.35 ( dd, J = 9.5, 5.7 Hz, 1H), 5.55 (q, J = 7.3 Hz, 1H), 4.68-4.59 (m, 5H), 2.75 (s, 6H), 2.66 (s, 3H), 2.11-2.03 (m, 2H), 1.96-1.85 (m, 1H), 1.70 (d, J = 7.1 Hz, 3H), 1.48 (s, 3H). LCMS [M+1] ⁺ : 466.3. 12-124

( R )-7-(3-(dimethylamino)-3-methylazetidin-1-yl) -N -(1-(4-fluoro-2-methylphenyl)ethyl Yl)-4-methylpyrido[3,4- d ]

-1-amine ¹ H NMR (400 MHz, CD ₃ OD) δ = 8.94 (s, 1H), 7.41 (dd, J = 8.6, 5.9 Hz, 1H), 7.02 (s, 1H), 6.90-6.77 (m, 2H), 5.56 (q, J = 6.9 Hz, 1H), 4.01 (d, J = 8.4 Hz, 2H), 3.88 (d, J = 8.4 Hz, 2H), 2.63 (s, 3H), 2.47 (s, 3H), 2.26 (s, 6H), 1.59 (d, J = 6.9 Hz, 3H), 1.44 (s, 3H). LCMS [M+1] ⁺ : 409.4. 12-125

N -(( R )-1-(3-fluoro-2-methylphenyl)ethyl)-7-(( S )-hexahydropyridine

And [2,1- c ][1,4]

-8(1 H )-yl)-4-methylpyrido[3,4- d ]

-1-amine dihydrochloride ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 15.02 (s, 1H), 12.35 (s, 1H), 9.48 (s, 1H), 9.30 (s, 1H), 8.48 (s, 1H), 7.47 (d, J = 7.8 Hz, 1H), 7.22-7.12 (m, 1H), 7.00 (t, J = 9.0 Hz, 1H), 5.39-5.31 (m, 1H), 5.15-5.03 (m, 2H), 4.27-4.20 (m, 1H), 4.03-3.95 (m, 2H), 3.79-3.71 (m, 3H), 3.35-3.06 (m, 2H), 3.59-3.55 (m, 2H), 2.80 (s, 3H) ), 2.37 (s, 3H), 1.66 (d, J = 7.0 Hz, 3H). LCMS [M+1] ⁺ : 473.3. 12-126

7-(6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)- N -(( R )-1-(3-fluoro-2-methylphenyl)ethyl)- 4-methylpyrido[3,4- d ]

-1-amine ¹ H NMR (400 MHz, CD ₃ OD) δ = 9.04 (s, 1H), 7.25 (d, J = 7.8 Hz, 1H), 7.20 (s, 1H), 7.13-7.03 (m, 1H), 6.91- 6.82 (m, 1H), 5.62 (q, J = 6.9 Hz, 1H), 4.87-4.81 (m, 2H), 3.99-3.91 (m, 2H), 3.85-3.76 (m, 2H), 3.38-3.32 ( m, 1H), 2.65 (s, 3H), 2.40-2.35 (m, 3H), 2.02 (d, 1H), 1.61 (d, J = 7.0 Hz, 3H). LCMS [M+1] ⁺ : 394.3. 12-127

3-(( R )-1-((7-((1 R ,4 R )-2-oxa-5-azabicyclo[2.2.1]hept-5-yl)-4-methylpyrido [3,4- d ]

-1-yl)amino)ethyl)-2-(trifluoromethyl)benzonitrile ¹ H NMR (400 MHz, CD ₃ OD) δ = 8.97 (s, 1H), 8.04 (d, J = 8.0 Hz, 1H), 7.79 (d, J =7.6 Hz, 1H), 7.70-7.59 (m, 1H), 7.10 (s, 1H), 5.72 (q, J = 6.4 Hz, 1H), 5.16 (br s, 1H), 4.81 (s, 1H), 3.96 (dd, J = 1.2, 7.2 Hz, 1H) , 3.87 (d, J = 7.2 Hz, 1H), 3.69 (dd, J = 1.2, 10.0 Hz, 1H), 3.52 (br d, J = 10.4 Hz, 1H), 2.59 (s, 3H), 2.07 (s , 2H), 1.67 (d, J = 6.8 Hz, 3H). LCMS [M+1] ⁺ : 455.3. 12-128

N-((R)-1-(4-amino-6-(difluoromethyl)pyridin-2-yl)ethyl)-7-((S)-hexahydropyridine

And [2,1-c][1,4]

-8(1H)-yl)-4-methylpyrido[3,4-d]

-1-amine ¹ H NMR (400 MHz, CD ₃ OD) δ = 8.99 (s, 1H), 7.28 (s, 1H), 6.67 (q, J = 2.2 Hz, 2H), 6.49 (t, J = 55.6 Hz, 1H) , 5.28 (q, J = 6.9 Hz, 1H), 4.56 (d, J = 13.1 Hz, 1H), 4.41 (d, J = 12.7 Hz, 1H), 3.91-3.81 (m, 2H), 3.72 (td, J = 11.5, 2.3 Hz, 1H), 3.36 (t, J = 10.7 Hz, 1H), 3.15 (td, J = 12.6, 3.1 Hz, 1H), 2.94 (d, J = 11.5 Hz, 1H), 2.78 ( d, J = 11.6 Hz, 1H), 2.71-2.64 (m, 1H), 2.63 (s, 3H), 2.46-2.29 (m, 3H), 1.62 (d, J = 7.0 Hz, 3H). LCMS [M+1] ⁺ : 471.5. 12-129

N -(( R )-1-(4-amino-6-(difluoromethyl)pyridin-2-yl)ethyl)-7-(6-oxa-3-azabicyclo[3.1.1 ]Hept-3-yl)-4-methylpyrido[3,4- d ]a

-1-amine ¹ H NMR (400 MHz, CD ₃ OD) δ = 9.06 (s, 1H), 7.15 (s, 1H), 6.73-6.68 (m, 2H), 6.52 (t, J = 55.7 Hz, 1H), 5.33 ( q, J = 6.9 Hz, 1H), 4.85 (s, 2H), 3.96 (t, J = 11.6 Hz, 2H), 3.82 (dd, J = 12.7, 5.2 Hz, 2H), 3.40-3.33 (m, 1H ), 2.67 (s, 3H), 2.05 (d, J = 9.0 Hz, 1H), 1.65 (d, J = 7.0 Hz, 3H). LCMS [M+1] ⁺ : 428.4. 12-130

( R )-1-(1-((1-(4-amino-6-(difluoromethyl)pyridin-2-yl)ethyl)amino)-4-methylpyrido[3,4 -d] Da

-7-yl)-3-methylazetidine-3-ol ¹ H NMR (400 MHz, CD ₃ OD) δ = 8.92 (s, 1H), 6.93 (s, 1H), 6.70 (s, 2H), 6.52 (t, J = 55.6 Hz, 1H), 5.29 (q, J = 6.9 Hz, 1H), 4.12-4.02 (m, 4H), 2.64 (s, 3H), 1.64 (d, J = 7.0 Hz, 3H), 1.60 (s, 3H). LCMS [M+1] ⁺ : 416.4. 12-131

N -(( R )-1-(2-fluoro-3-methylphenyl)ethyl)-7-(( S )-hexahydropyridine

And [2,1- c ][1,4]

-8(1 H )-yl)-4-methylpyrido[3,4- d ]

-1-amine ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 8.97 (s, 1H), 8.31 (s, 1H), 7.41 (s, 1H), 7.36 (d, J = 7.2 Hz, 1H), 7.18 (t , J = 7.2 Hz, 1H), 7.09-7.04 (m, 1H), 6.95 (t, J = 7.6 Hz, 1H), 5.66-5.62 (m, 1H), 4.44-4.36 (m, 2H), 3.89- 3.75 (m, 2H), 3.58-3.54 (m, 1H), 3.21-3.20 (m, 1H), 3.11-3.05 (m, 1H), 2.91 (d, J = 11.2 Hz, 1H), 2.72 (d, J = 11.6 Hz, 1H), 2.57-2.56 (m, 1H), 2.55 (s, 3H), 2.30-2.26 (m, 1H), 2.24 (s, 3H), 2.22-2.15 (m, 2H), 1.56 (d, J = 7.2 Hz, 3H). LCMS [M+1] ⁺ : 437.1. 12-132

( R )-1-(1-((1-(2-Fluoro-3-methylphenyl)ethyl)amino)-4-methylpyrido[3,4- d ]

-7-yl)-3-methylazetidine-3-ol ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.95 (s, 1H), 7.33 (d, J = 7.4 Hz, 1H), 7.18 (t, J = 7.2 Hz, 1H), 7.13-7.06 (m, 2H), 6.96 (t, J = 7.6 Hz, 1H), 5.71 (s, 1H), 5.64 (q, J = 7.0 Hz, 1H), 4.05-3.92 (m, 4H), 2.54 (s, 3H), 2.25 (s, 3H), 1.56 (d, J = 7.0 Hz, 3H), 1.49 (s, 3H). LCMS [M+1] ⁺ : 382.3. 12-133

( R )-7-(3-(dimethylamino)-3-methylazetidin-1-yl) -N -(1-(2-fluoro-3-methylphenyl)ethyl Yl)-4-methylpyrido[3,4- d ]

-1-amine ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.94 (s, 1H), 8.28 (s, 0H), 7.32 (d, J = 7.3 Hz, 1H), 7.19 (t, J = 7.6 Hz, 1H) , 7.10 (d, J = 4.2 Hz, 2H), 6.96 (t, J = 7.5 Hz, 1H), 5.62 (q, J = 6.9 Hz, 1H), 3.89 (dd, J = 8.2, 5.2 Hz, 2H) , 3.79 (dd, J = 8.1, 3.2 Hz, 2H), 2.54 (s, 3H), 2.24 (s, 3H), 2.15 (s, 6H), 1.56 (d, J = 7.0 Hz, 3H), 1.32 ( s, 3H). LCMS [M+1] ⁺ : 409.4. 12-134

7-(6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)- N -(( R )-1-(2-fluoro-3-methylphenyl)ethyl)- 4-methylpyrido[3,4- d ]

-1-amine ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.04 (s, 1H), 7.45 (d, J = 7.4 Hz, 1H), 7.28 (s, 1H), 7.21 (t, J = 7.3 Hz, 1H) , 7.09 (t, J = 7.2 Hz, 1H), 6.96 (t, J = 7.6 Hz, 1H), 5.67 (t, J = 7.1 Hz, 1H), 4.81 (d, J = 6.4 Hz, 2H), 3.95 -3.85 (m, 2H), 3.77-3.67 (m, 2H), 2.57 (s, 3H), 2.25 (s, 3H), 1.95 (d, J = 8.8 Hz, 1H), 1.57 (d, J = 7.0 Hz, 3H). LCMS [M+1] ⁺ : 394.0. Example 13-1 4-methyl-N -((R )-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-7-(((S )-Tetrahydrofuran-3-yl)oxy) 呔

-1-amine

-1-胺（70.0 mg，164 µmol，1.00當量）於甲苯（1.00 mL）中之溶液中添加氫化鈉（13.2 mg，329 µmol，60.0%於礦物油中，2.00當量），隨後向混合物添加(S )-四氫呋喃-3-醇（43.6 mg，494 µmol，3.00當量）、Pd₂ (dba)₃ （15.1 mg，16.5 µmol，0.10當量）及Tol-BINAP（22.4 mg，33.0 µmol，0.20當量）。將反應混合物溫熱至100℃，且在氮氣氛圍下攪拌1小時。在此時間後，將混合物冷卻至25℃，用飽和氯化銨水溶液（30.0 mL）緩慢淬滅，隨後用乙酸乙酯（20.0 mL×3）萃取。將合併之有機相用鹽水（30.0 mL）洗滌，經無水硫酸鈉乾燥，過濾，並真空濃縮，得到殘餘物。將殘餘物藉由製備型HPLC（管柱：Phenomenex luna C18 80×40 mm×3 µm；移動相：A相：含0.04% HCl的水，B相：乙腈；B%的梯度：30%-52%）純化，得到呈白色固體狀之4-甲基-N -((R )-1-(2-甲基-3-(三氟甲基)苯基)乙基)-7-(((S )-四氫呋喃-3-基)氧基)呔

-1-胺（6.31 mg，14.0 µmol，8.5%產率，HCl鹽）。LCMS [M+1]⁺ : 432.1In a nitrogen atmosphere at 0℃, to ( R )-7-bromo-4-methyl- N -(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)

-1-amine (70.0 mg, 164 µmol, 1.00 equivalent) in toluene (1.00 mL) was added sodium hydride (13.2 mg, 329 µmol, 60.0% in mineral oil, 2.00 equivalent), and then added to the mixture ( S )-tetrahydrofuran-3-ol (43.6 mg, 494 µmol, 3.00 equivalents), Pd ₂ (dba) ₃ (15.1 mg, 16.5 µmol, 0.10 equivalents) and Tol-BINAP (22.4 mg, 33.0 µmol, 0.20 equivalents). The reaction mixture was warmed to 100°C and stirred under a nitrogen atmosphere for 1 hour. After this time, the mixture was cooled to 25°C, slowly quenched with saturated aqueous ammonium chloride (30.0 mL), and then extracted with ethyl acetate (20.0 mL×3). The combined organic phase was washed with brine (30.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to obtain a residue. The residue was subjected to preparative HPLC (column: Phenomenex luna C18 80×40 mm×3 µm; mobile phase: phase A: water containing 0.04% HCl, phase B: acetonitrile; gradient of B%: 30%-52 %) purified to obtain 4-methyl- N -(( R )-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-7-((( S )-tetrahydrofuran-3-yl)oxy) 呔

-1-amine (6.31 mg, 14.0 µmol, 8.5% yield, HCl salt). LCMS [M+1] ⁺ : 432.1

¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 15.31 (s, 1H), 8.91 (s, 1H), 8.90-8.34 (m, 2H), 7.82-7.77 (m, 2H), 7.56 (d, J = 8.0 Hz, 1H), 7.35 (t, J = 8.0 Hz, 1H), 5.56 (s, 1H), 5.52-5.47 (m, 1H), 4.05-4.03 (m, 1H), 3.93-3.84 (m , 3H), 2.79 (s, 3H), 2.58 (s, 3H), 2.45-2.43 (m, 1H), 2.08-2.06 (m, 1H), 1.63 (d, J = 7.2 Hz, 3H).

-1-胺

SFC conditions: Chiralcel OD-3 3µm, 0.46 cm inner diameter×5 cm L; mobile phase: MeOH (0.05% isopropylamine); gradient: B in A increased from 10% to 40% within 3 minutes; flow rate: 4.0 ml /Min; Column temperature: 35°C; Wavelength: 220 nm Example 13-2 ( R )-4-methyl- N -(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl )-7-(oxetan-3-yloxy)

-1-amine

-1-胺（100 mg，236 µmol，1.00當量）、氧雜環丁烷-3-醇（26.2 mg，354 µmol，1.50當量）、第三丁醇鈉（68.0 mg，707 µmol，3.00當量）及[2-(2-胺基苯基)苯基]-甲基磺醯氧基-鈀；二第三丁基-[2-(2,4,6-三異丙基苯基)苯基]膦（18.7 mg，23.6 µmol，0.10當量）於二

烷（2.00 mL）中之混合物脫氣且用氮氣沖洗3次，隨後將混合物在氮氣氛圍下在100℃下攪拌1小時。將混合物過濾且真空濃縮，得到殘餘物。將殘餘物藉由製備型TLC（SiO₂ ，二氯甲烷/甲醇＝20/1）純化，隨後藉由製備型HPLC（管柱：Phenomenex luna C18 150×25 mm×10 um；移動相：A相：水（0.225% TFA），B相：乙腈；B相梯度：17%-47%）純化，得到呈灰白色固體狀之(R )-4-甲基-N -(1-(2-甲基-3-(三氟甲基)苯基)乙基)-7-(氧雜環丁烷-3-基氧基)呔

-1-胺（5.20 mg，12.4 µmol，5.25產率，%產率，99.4%純度）。LCMS [M+1]⁺ : 418.0。Add ( R )-7-bromo-4-methyl- N -(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)

-1-amine (100 mg, 236 µmol, 1.00 equivalent), oxetane-3-ol (26.2 mg, 354 µmol, 1.50 equivalent), sodium tert-butoxide (68.0 mg, 707 µmol, 3.00 equivalent) And [2-(2-aminophenyl)phenyl]-methylsulfonyloxy-palladium; di-tert-butyl-[2-(2,4,6-triisopropylphenyl)phenyl ] Phosphine (18.7 mg, 23.6 µmol, 0.10 equivalent) in two

The mixture in alkane (2.00 mL) was degassed and flushed with nitrogen 3 times, then the mixture was stirred at 100°C for 1 hour under a nitrogen atmosphere. The mixture was filtered and concentrated in vacuo to give a residue. The residue was purified by preparative TLC (SiO ₂ , dichloromethane/methanol = 20/1), followed by preparative HPLC (column: Phenomenex luna C18 150×25 mm×10 um; mobile phase: Phase A : Water (0.225% TFA), phase B: acetonitrile; phase B gradient: 17%-47%) to obtain ( R )-4-methyl- N -(1-(2-methyl) as an off-white solid -3-(trifluoromethyl)phenyl)ethyl)-7-(oxetan-3-yloxy)

-1-amine (5.20 mg, 12.4 µmol, 5.25 yield,% yield, 99.4% purity). LCMS [M+1] ⁺ : 418.0.

¹ H NMR (400 MHz, CD ₃ OD) δ = 8.19 (d, J = 8.8 Hz, 1H), 7.78-7.73 (m, 1H), 7.71 (d, J = 8.0 Hz, 1H), 7.61-7.56 ( m, 1H), 7.52 (d, J = 7.6 Hz, 1H), 7.26 (t, J = 8.0 Hz, 1H), 5.69-5.59 (m, 2H), 5.21-5.12 (m, 2H), 4.81-4.75 (m, 2H), 2.75 (s, 3H), 2.63 (s, 3H), 1.67 (d, J = 7.2 Hz, 3H).

2-甲基-3-((R )-1-((4-甲基-7-(((S )-四氫呋喃-3-基)氧基)呔

-1-基)胺基)乙基)苯甲腈 ¹ H NMR (400 MHz, CD₃ OD) = 8.04 (d,J = 9.2 Hz, 1H), 7.81 (d,J = 2.4 Hz, 1H), 7.73 (d,J = 7.6 Hz, 1H), 7.54 - 7.48 (m, 2H), 7.25 (t,J = 8.0 Hz, 1H), 5.66 - 5.55 (m, 1H), 5.38 - 5.33 (m, 1H), 4.12 - 4.05 (m, 1H), 4.04 - 3.99 (m, 2H), 3.98 - 3.91 (m, 1H), 2.75 (s, 3H), 2.67 (s, 3H), 2.46 - 2.35 (m, 1H), 2.25 - 2.17 (m, 1H), 1.63 (d,J = 7.2 Hz, 3H)。 LCMS [M+1]⁺ : 389.1。 實例14-1

Following the teaching of General Reaction Scheme III and the methods of preparing Examples 13-1 and 13-2, the following compounds of formula (I), Example 13-3, as shown in Table 13 were prepared. Table 13 Example # structure Spectral data 13-3

2-Methyl-3-(( R )-1-((4-methyl-7-((( S )-tetrahydrofuran-3-yl)oxy)

-1-yl)amino)ethyl)benzonitrile ¹ H NMR (400 MHz, CD ₃ OD) = 8.04 (d, J = 9.2 Hz, 1H), 7.81 (d, J = 2.4 Hz, 1H), 7.73 (d, J = 7.6 Hz, 1H), 7.54- 7.48 (m, 2H), 7.25 (t, J = 8.0 Hz, 1H), 5.66-5.55 (m, 1H), 5.38-5.33 (m, 1H), 4.12-4.05 (m, 1H), 4.04-3.99 ( m, 2H), 3.98-3.91 (m, 1H), 2.75 (s, 3H), 2.67 (s, 3H), 2.46-2.35 (m, 1H), 2.25-2.17 (m, 1H), 1.63 (d, J = 7.2 Hz, 3H). LCMS [M+1] ⁺ : 389.1. Example 14-1

（500 mg，1.94 mmol，1.00當量）於氯仿（8.00 mL）中之溶液中添加NBS（380 mg，2.14 mmol，1.10當量）及AIBN（48.0 mg，0.29 mmol，0.15當量），且將反應混合物在90℃下攪拌3小時。隨後將反應混合物冷卻至25℃，用水（20.0 mL）淬滅，且用乙酸乙酯（30.0 mL×3）萃取。將合併之有機層用鹽水（25.0 mL×2）洗滌，經硫酸鈉乾燥，過濾，且在減壓下濃縮，得到殘餘物。將殘餘物藉由管柱層析法（SiO₂ ，石油醚/乙酸乙酯＝10/1至1/1）純化，得到呈黃色固體狀之6-溴-1-(溴甲基)-4-氯呔

（180 mg，535 µmol，產率27.6%）。LCMS [M+3]⁺ : 336.6。Step A: Add 6 6-bromo-4-chloro-1-methyl

(500 mg, 1.94 mmol, 1.00 equivalent) in chloroform (8.00 mL) was added NBS (380 mg, 2.14 mmol, 1.10 equivalent) and AIBN (48.0 mg, 0.29 mmol, 0.15 equivalent), and the reaction mixture was Stir at 90°C for 3 hours. The reaction mixture was then cooled to 25°C, quenched with water (20.0 mL), and extracted with ethyl acetate (30.0 mL×3). The combined organic layer was washed with brine (25.0 mL×2), dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 10/1 to 1/1) to obtain 6-bromo-1-(bromomethyl)-4 as a yellow solid -Chlorine

(180 mg, 535 µmol, 27.6% yield). LCMS [M+3] ⁺ : 336.6.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 8.52-8.50 (m, 1H), 8.41 (dd, J = 1.2, 3.6 Hz, 2H), 5.42 (s, 1H), 5.31 (s, 1H) .

（180 mg，0.54 mmol，1.00當量）添加至該反應混合物中，且將混合物在25℃下攪拌12小時。將混合物用水（30.0 mL）稀釋，且用乙酸乙酯（30.0 mL×3）萃取。將合併之有機層用鹽水（30.0 mL×2）洗滌，經硫酸鈉乾燥，過濾，且在減壓下濃縮，得到殘餘物。將殘餘物藉由製備型TLC（SiO₂ ，石油醚/乙酸乙酯＝1/1，Rf＝0.4）純化，得到呈黃色固體狀之1-(6-溴-4-氯呔

-1-基)-N ,N -二甲基甲胺（80.0 mg，266 µmol，49.7%）。LCMS [M+3]⁺ : 301.9Step B: To a solution of dimethylamine (48.2 mg, 1.07 mmol, 0.05 mL, 2.00 equivalents, HCl salt) in tetrahydrofuran (10.0 mL) was added N , N -diisopropylethylamine (207 mg, 1.61 mmol) , 0.28 mL, 3.00 equivalents), followed by 6-bromo-1-(bromomethyl)-4-chloro

(180 mg, 0.54 mmol, 1.00 equivalent) was added to the reaction mixture, and the mixture was stirred at 25°C for 12 hours. The mixture was diluted with water (30.0 mL), and extracted with ethyl acetate (30.0 mL×3). The combined organic layer was washed with brine (30.0 mL×2), dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by preparative TLC (SiO ₂ , petroleum ether/ethyl acetate = 1/1, Rf = 0.4) to obtain 1-(6-bromo-4-chlorobenzene as a yellow solid)

-1-yl) -N , N -dimethylmethylamine (80.0 mg, 266 µmol, 49.7%). LCMS [M+3] ⁺ : 301.9

¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 8.51 (d, J = 8.8 Hz, 1H), 8.44 (d, J = 1.6 Hz, 1H), 8.30 (dd, J = 2.0, 8.8 Hz, 1H ), 4.02 (s, 2H), 2.22 (s, 6H).

-1-基)-N ,N -二甲基甲胺（120 mg，0.40 mmol，1.00當量）及(R )-1-(2-甲基-3-(三氟甲基)苯基)乙-1-胺（89.2 mg，0.44 mmol，1.10當量）於二甲基亞碸（3.00 mL）中之溶液中添加氟化鉀（69.6 mg，1.20 mmol，0.03 mL，3.00當量），隨後將反應在130℃下攪拌2小時。將反應冷卻至25℃，用水（20.0 mL）淬滅，且用乙酸乙酯（20.0 mL×3）萃取。將合併之有機層用鹽水（20.0 mL×2）洗滌，經硫酸鈉乾燥，過濾，且在減壓下濃縮，得到殘餘物。將殘餘物藉由製備型TLC（SiO₂ ，石油醚/乙酸乙酯＝1/1，Rf＝0.2）純化，得到呈黃色油狀之(R )-7-溴-4-((二甲基胺基)甲基)-N -(1-(2-甲基-3-(三氟甲基)苯基)乙基)呔

-1-胺（90.0 mg，192 µmol，48.2%產率）。LCMS [M+1]⁺ : 467.0。Step C: To 1-(6-bromo-4-chloro

-1-yl) -N , N -dimethylmethylamine (120 mg, 0.40 mmol, 1.00 equivalent) and ( R )-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl -1-amine (89.2 mg, 0.44 mmol, 1.10 equivalents) in dimethyl sulfoxide (3.00 mL) was added potassium fluoride (69.6 mg, 1.20 mmol, 0.03 mL, 3.00 equivalents), and then the reaction was Stir at 130°C for 2 hours. The reaction was cooled to 25°C, quenched with water (20.0 mL), and extracted with ethyl acetate (20.0 mL×3). The combined organic layer was washed with brine (20.0 mL×2), dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by preparative TLC (SiO ₂ , petroleum ether/ethyl acetate = 1/1, Rf = 0.2) to obtain ( R )-7-bromo-4-((dimethyl Amino)methyl) -N -(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)

-1-amine (90.0 mg, 192 µmol, 48.2% yield). LCMS [M+1] ⁺ : 467.0.

-1-胺（60.0 mg，0.13 mmol，1.00當量）、

啉（28.0 mg，0.32 mmol，0.03 mL，2.50當量）、碳酸銫（125 mg，0.39 mmol，3.00當量）及RuPhos（12.0 mg，0.03 mmol，0.20當量）於二

烷（8.00 mL）中之溶液中添加Pd₂ (dba)₃ （11.8 mg，0.02 mmol，0.10當量），隨後脫氣且用氮氣沖洗3次，且將反應混合物在氮氣氛圍下在100℃下攪拌2小時。將反應冷卻至25℃，用水（20.0 mL）稀釋，且用乙酸乙酯（30.0 mL×3）萃取。將合併之有機層用鹽水（25.0 mL×2）洗滌，經硫酸鈉乾燥，過濾，且在減壓下濃縮，得到殘餘物。將殘餘物藉由製備型TLC（SiO₂ ，石油醚/乙酸乙酯＝1/1）純化，得到呈黃色固體狀之(R )-4-((二甲基胺基)甲基)-N -(1-(2-甲基-3-(三氟甲基)苯基)乙基)-7-

啉基呔

-1-胺（5.75 mg，12.1 µmol，9.45%產率，99.9%純度）。LCMS [M+1]⁺ : 474.3。Step D: To ( R )-7-bromo-4-((dimethylamino)methyl) -N -(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl ) Eh

-1-amine (60.0 mg, 0.13 mmol, 1.00 equivalent),

Morpholine (28.0 mg, 0.32 mmol, 0.03 mL, 2.50 equivalents), cesium carbonate (125 mg, 0.39 mmol, 3.00 equivalents) and RuPhos (12.0 mg, 0.03 mmol, 0.20 equivalents) in two

_{Pd 2} (dba) ₃ (11.8 mg, 0.02 mmol, 0.10 equivalent) was added to the solution in alkane (8.00 mL), then degassed and flushed with nitrogen 3 times, and the reaction mixture was stirred at 100°C under a nitrogen atmosphere 2 hours. The reaction was cooled to 25°C, diluted with water (20.0 mL), and extracted with ethyl acetate (30.0 mL×3). The combined organic layer was washed with brine (25.0 mL×2), dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by preparative TLC (SiO ₂ , petroleum ether/ethyl acetate = 1/1) to obtain ( R )-4-((dimethylamino)methyl) -N as a yellow solid -(1-(2-Methyl-3-(trifluoromethyl)phenyl)ethyl)-7-

Linyl

-1-amine (5.75 mg, 12.1 µmol, 9.45% yield, 99.9% purity). LCMS [M+1] ⁺ : 474.3.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 8.09 (d, J = 8.8 Hz, 1H), 7.76 (d, J = 8.0 Hz, 1H), 7.62 (s, 1H), 7.58 (dd, J = 2.0, 8.8 Hz, 1H), 7.52 (br d, J = 7.2 Hz, 2H), 7.32 (t, J = 7.6 Hz, 1H), 5.77-5.67 (m, 1H), 3.86-3.80 (m, 4H ), 3.45-3.40 (m, 4H), 3.31 (br s, 2H), 2.58 (s, 3H), 2.16 (br s, 6H), 1.56 (d, J = 7.2 Hz, 3H).

SFC conditions: Chiralcel OD-3 50×4.6 mm inner diameter, 3 um; mobile phase: A phase is CO ₂ , and B phase is MeOH (0.05% DEA), gradient dissolution: MeOH (0.05% DEA) at 5% to In 40% CO ₂ ; flow rate: 3 ml/min, detector: PDA, column temperature: 35°C, back pressure: 100 Bar. Example 14-2

（150 mg，446 µmol，1.00當量）於二甲基甲醯胺（15.0 mL）中之混合物中添加鄰苯二甲醯亞胺鉀（116 mg，624 µmol，1.40當量）。將混合物在85℃下攪拌2小時，隨後冷卻至25℃。隨後將混合物用水（50.0 mL）稀釋，且用乙酸乙酯（50.0 mL×3）萃取。將合併之有機相用鹽水（100 mL）洗滌，經無水硫酸鈉乾燥，過濾，且在真空下濃縮，得到殘餘物。將殘餘物藉由管柱層析法（SiO₂ ，石油醚/乙酸乙酯＝5/1）純化，得到呈黃色固體狀之2-((6-溴-4-氯呔

-1-基)甲基)異吲哚啉-1,3-二酮（150 mg，373 µmol，83.6%產率）。LCMS [M+1]⁺ : 404.0。Step A: Add 6-bromo-1-(bromomethyl)-4-chlorobenzene to 6-bromo-1-(bromomethyl)-4-chloro-

(150 mg, 446 µmol, 1.00 equivalent) Potassium phthalimide (116 mg, 624 µmol, 1.40 equivalent) was added to the mixture in dimethylformamide (15.0 mL). The mixture was stirred at 85°C for 2 hours and then cooled to 25°C. The mixture was then diluted with water (50.0 mL), and extracted with ethyl acetate (50.0 mL×3). The combined organic phase was washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 5/1) to obtain 2-((6-bromo-4-chloroacetate) as a yellow solid

-1-yl)methyl)isoindoline-1,3-dione (150 mg, 373 µmol, 83.6% yield). LCMS [M+1] ⁺ : 404.0.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 8.55 (m, 2H), 8.40 (m, 1H), 7.95 (m, 2H), 7.90 (m, 2H), 5.60 (s, 2H).

-1-基)甲基)異吲哚啉-1,3-二酮（130 mg，323 µmol，1.00當量）及(R )-1-(2-甲基-3-(三氟甲基)苯基)乙-1-胺（65.6 mg，323 µmol，1.00當量）於二甲基亞碸（7.00 mL）中之溶液中添加N,N- 二異丙基乙胺（125 mg，969 µmol，169 µL，3.00當量）及氟化鉀（56.3 mg，969 µmol，22.7 µL，3.00當量），將其於密閉管中在130℃下攪拌12小時。將反應冷卻至25℃，且用水（50.0 mL）稀釋，且用乙酸乙酯（50.0 mL×3）萃取。將合併之有機相用鹽水（100 mL）洗滌，經硫酸鈉乾燥，過濾，且在減壓下濃縮，得到殘餘物。將殘餘物藉由管柱層析法（SiO₂ ，石油醚/乙酸乙酯＝5/1）純化，得到呈黃色固體狀之(R )-2-((6-溴-4-((1-(2-甲基-3-(三氟甲基)苯基)乙基)胺基)呔

-1-基)甲基)異吲哚啉-1,3-二酮（130 mg，228 µmol，70.7%產率）。LCMS [M+1]⁺ : 472.2。Step B: To 2-((6-bromo-4-chloro

-1-yl)methyl)isoindoline-1,3-dione (130 mg, 323 µmol, 1.00 equivalent) and ( R )-1-(2-methyl-3-(trifluoromethyl) Phenyl) ethyl-1-amine (65.6 mg, 323 µmol, 1.00 equivalent) was added to a solution of dimethyl sulfide (7.00 mL) with N,N -diisopropylethylamine (125 mg, 969 µmol, 169 µL, 3.00 equivalents) and potassium fluoride (56.3 mg, 969 µmol, 22.7 µL, 3.00 equivalents) were stirred in a closed tube at 130°C for 12 hours. The reaction was cooled to 25°C, and diluted with water (50.0 mL), and extracted with ethyl acetate (50.0 mL×3). The combined organic phase was washed with brine (100 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 5/1) to obtain ( R )-2-((6-bromo-4-((1 -(2-Methyl-3-(trifluoromethyl)phenyl)ethyl)amino)

-1-yl)methyl)isoindoline-1,3-dione (130 mg, 228 µmol, 70.7% yield). LCMS [M+1] ⁺ : 472.2.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 8.91 (s, 1H), 8.20-8.07 (m, 2H), 7.97-7.80 (m, 5H), 7.74 (d, J = 8.0 Hz, 1H) , 7.51 (d, J = 8.0 Hz, 1H), 7.31 (t, J = 8.0 Hz, 1H), 5.72-5.60 (m, 1H), 5.25 (s, 2H), 2.44 (s, 3H), 1.50 ( d, J = 7.2 Hz, 3H).

-1-基)甲基)異吲哚啉-1,3-二酮（100 mg，176 µmol，1.00當量）及

啉（61.2 mg，703 µmol，61.8 µL，4.00當量）於甲苯（10.0 mL）中之溶液中添加BINAP（21.9 mg，35.1 µmol，0.20當量）、碳酸銫（172 mg，527 µmol，3.00當量）及Pd₂ (dba)₃ （16.1 mg，17.6 µmol，0.10當量）。將混合物在100℃下攪拌1小時。反應完成且冷卻至25℃。將反應混合物用水（50.0 mL）淬滅，且用乙酸乙酯（50.0 mL×3）萃取。將合併之有機相用鹽水（100 mL）洗滌，經硫酸鈉乾燥，過濾，且在減壓下濃縮，得到殘餘物。將殘餘物藉由管柱層析法（SiO₂ ，石油醚/乙酸乙酯＝1/1）純化，得到呈黃色固體狀之(R )-2-((4-((1-(2-甲基-3-(三氟甲基)苯基)乙基)胺基)-6-

啉基呔

-1-基)甲基)異吲哚啉-1,3-二酮（65.0 mg，113 µmol，64.3%產率）。LCMS [M+1]⁺ : 576.3。Step C: Under nitrogen atmosphere at 25°C, add ( R )-2-((6-bromo-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl )Amino)

-1-yl)methyl)isoindoline-1,3-dione (100 mg, 176 µmol, 1.00 equivalent) and

Add BINAP (21.9 mg, 35.1 µmol, 0.20 equivalent), cesium carbonate (172 mg, 527 µmol, 3.00 equivalent) and Pd ₂ (dba) ₃ (16.1 mg, 17.6 µmol, 0.10 equivalent). The mixture was stirred at 100°C for 1 hour. The reaction was completed and cooled to 25°C. The reaction mixture was quenched with water (50.0 mL), and extracted with ethyl acetate (50.0 mL×3). The combined organic phase was washed with brine (100 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 1/1) to obtain ( R )-2-((4-((1-(2- Methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-6-

Linyl

-1-yl)methyl)isoindoline-1,3-dione (65.0 mg, 113 µmol, 64.3% yield). LCMS [M+1] ⁺ : 576.3.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 8.03 (br d, J = 10.0 Hz, 1H), 7.94-7.85 (m, 4H), 7.74 (br d, J = 7.2 Hz, 1H), 7.65 (br s, 2H), 7.51 (br d, J = 8.0 Hz, 1H), 7.43 (br d, J = 7.2 Hz, 1H), 7.31 (br t, J = 6.8 Hz, 1H), 5.72-5.67 ( m, 1H), 5.18 (s, 2H), 3.83 (m, 4H), 3.45 (m, 4H), 2.44 (s, 3H), 1.51 (d, J = 7.2 Hz, 3H).

啉基呔

-1-基)甲基)異吲哚啉-1,3-二酮（60.0 mg，104 µmol，1.00當量）於乙醇（6.00 mL）中之溶液中添加水合肼（47.0 mg，938 µmol，45.6 µL，9.00當量）。將混合物在25℃下攪拌1小時，隨後用水（10.0 mL）淬滅且用乙酸乙酯（10.0 mL×3）萃取。將合併之有機層用鹽水（30.0 mL）洗滌，經硫酸鈉乾燥，過濾，且在減壓下濃縮，得到殘餘物。將粗產物藉由逆相HPLC（水（0.04% HCl）/CH₃ CN）純化，得到呈黃色固體狀之(R )-4-(胺基甲基)-N-(1-(2-甲基-3-(三氟甲基)苯基)乙基)-7-

啉基呔

-1-胺（5.81 mg，13.0 µmol，12.5%產率，鹽酸鹽）。LCMS [M+1]⁺ : 446.1。Step D: Under nitrogen atmosphere at 25°C, to ( R )-2-((4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino) -6-

Linyl

-1-yl)methyl)isoindoline-1,3-dione (60.0 mg, 104 µmol, 1.00 equivalent) in ethanol (6.00 mL) was added with hydrazine hydrate (47.0 mg, 938 µmol, 45.6 µL, 9.00 equivalent). The mixture was stirred at 25°C for 1 hour, then quenched with water (10.0 mL) and extracted with ethyl acetate (10.0 mL×3). The combined organic layer was washed with brine (30.0 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The crude product was purified by reverse phase HPLC (water (0.04% HCl)/CH ₃ CN) to obtain ( R )-4-(aminomethyl)-N-(1-(2-methyl) as a yellow solid 3-(trifluoromethyl)phenyl)ethyl)-7-

Linyl

-1-amine (5.81 mg, 13.0 µmol, 12.5% yield, hydrochloride). LCMS [M+1] ⁺ : 446.1.

-1-基)胺基)乙基)-2-甲基苯甲腈

¹ H NMR (400MHz, DMSO-d ₆ ) δ = 8.62 (br s, 3H), 8.12 (br s, 2H), 7.79 (br d, J = 7.6 Hz, 2H), 7.61 (br d, J = 8.0 Hz, 1H), 7.38 (br t, J = 8.0 Hz, 1H), 5.66 (br d, J = 6.4 Hz, 1H), 4.56 (br s, 2H), 3.81 (br t, J = 4.8 Hz, 4H ), 3.62 (br s, 4H), 2.53 (m, 3H), 1.70 (br d, J = 5.6 Hz, 3H). Example 14-3 3-(( R )-1-((7-((1 R ,4 R )-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-4- ((Methylamino)methyl)pyrido[3,4- d ]

-1-yl)amino)ethyl)-2-methylbenzonitrile

-1-基)胺基)乙基)-2-甲基苯甲腈（30.0 mg，88.8 µmol，1.00 當量）於二

烷（1.00 mL）中之溶液中添加二氧化硒（19.7 mg，178 µmol，19.3 µL，2.00當量），且將混合物在100℃下攪拌1小時。隨後將混合物在減壓下濃縮，且將殘餘物藉由管柱層析法（SiO₂ ，石油醚/乙酸乙酯=20/1至5/1）純化，得到呈黃色固體狀之(R )-3-(1-((7-氯-4-甲醯基吡啶并[3,4-d ]嗒

-1-基)胺基)乙基)-2-甲基苯甲腈（16.0 mg，45.5 µmol，51.2%產率）。Step A: To ( R )-3-(1-((7-chloro-4-methylpyrido[3,4- d ]

-1-yl)amino)ethyl)-2-methylbenzonitrile (30.0 mg, 88.8 µmol, 1.00 equivalent) in two

Selenium dioxide (19.7 mg, 178 µmol, 19.3 µL, 2.00 equivalents) was added to the solution in alkane (1.00 mL), and the mixture was stirred at 100°C for 1 hour. The mixture was then concentrated under reduced pressure, and the residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 20/1 to 5/1) to obtain ( R ) as a yellow solid -3-(1-((7-chloro-4-methylpyrido[3,4- d ]

-1-yl)amino)ethyl)-2-methylbenzonitrile (16.0 mg, 45.5 µmol, 51.2% yield).

¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 10.06 (s, 1H), 9.99 (s, 1H), 9.09 (br d, J = 6.8 Hz, 1H), 8.76 (s, 1H), 7.78 ( br d, J = 8.0 Hz, 1H), 7.66 (br d, J = 7.6 Hz, 1H), 7.36 (br t, J = 8.0 Hz, 1H), 5.81 (br d, J = 6.4 Hz, 1H), 2.69 (s, 3H), 1.63 (br d, J = 6.8 Hz, 3H).

-1-基)胺基)乙基)-2-甲基苯甲腈（106 mg，301 µmol，1.00當量）及甲胺四氫呋喃溶液（2.0 M，360 µL，2.39當量）於THF（3.00 mL）中之溶液中添加乙酸（1.81 mg，30.1 µmol，1.72 µL，0.10當量），且將混合物在50℃下攪拌30分鐘。在此時間後，添加三乙醯氧基硼氫化鈉（192 mg，904 µmol，3.00當量），且不久後將混合物倒入水（5.00 mL）中。用乙酸乙酯（10.0 mL×3）萃取水相，且將合併之有機相用鹽水（10.0 mL×2）洗滌，經無水硫酸鈉乾燥，過濾，且在減壓下濃縮，得到呈黃色固體狀之(R )-3-(1-((7-氯-4-((甲基胺基)甲基)吡啶并[3,4-d ]嗒

-1-基)胺基)乙基)-2-甲基苯甲腈（65.0 mg，177 µmol，58.8%產率）。LCMS [M+1]⁺ : 367.2。Step B: Add ( R )-3-(1-((7-chloro-4-methylpyrido[3,4- d ]

-1-yl)amino)ethyl)-2-methylbenzonitrile (106 mg, 301 µmol, 1.00 equivalent) and methylamine tetrahydrofuran solution (2.0 M, 360 µL, 2.39 equivalent) in THF (3.00 mL) Acetic acid (1.81 mg, 30.1 µmol, 1.72 µL, 0.10 equivalent) was added to the solution in the solution, and the mixture was stirred at 50°C for 30 minutes. After this time, sodium triacetoxyborohydride (192 mg, 904 µmol, 3.00 equivalents) was added, and soon the mixture was poured into water (5.00 mL). The aqueous phase was extracted with ethyl acetate (10.0 mL×3), and the combined organic phase was washed with brine (10.0 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a yellow solid The ( R )-3-(1-((7-chloro-4-((methylamino)methyl)pyrido[3,4- d ]

-1-yl)amino)ethyl)-2-methylbenzonitrile (65.0 mg, 177 µmol, 58.8% yield). LCMS [M+1] ⁺ : 367.2.

-1-基)胺基)乙基)-2-甲基苯甲腈（34.0 mg，92.7 µmol，1.00當量）及(Boc)₂ O（22.3 mg，102 µmol，23.4 µL，1.10當量）於DCM（0.50 mL）中之溶液中添加DMAP（1.13 mg，9.27 µmol，0.10當量），且將混合物在25℃下攪拌1小時。隨後將混合物在減壓下濃縮，且將殘餘物藉由製備型TLC（SiO₂ ，石油醚/乙酸乙酯= 2:1）純化，得到呈黃色固體狀之(R )-((7-氯-1-((1-(3-氰基-2-甲基苯基)乙基)胺基)吡啶并[3,4-d ]嗒

-4-基)甲基)(甲基)胺甲酸第三丁酯（35.0 mg，75.0 µmol，80.9%產率）。Step C: To ( R )-3-(1-((7-chloro-4-((methylamino)methyl)pyrido[3,4- d ]

-1-yl)amino)ethyl)-2-methylbenzonitrile (34.0 mg, 92.7 µmol, 1.00 equivalent) and (Boc) ₂ O (22.3 mg, 102 µmol, 23.4 µL, 1.10 equivalent) in DCM DMAP (1.13 mg, 9.27 µmol, 0.10 equivalent) was added to the solution in (0.50 mL), and the mixture was stirred at 25°C for 1 hour. The mixture was then concentrated under reduced pressure, and the residue was purified by preparative TLC (SiO ₂ , petroleum ether/ethyl acetate = 2:1) to obtain ( R )-((7-chloro -1-((1-(3-cyano-2-methylphenyl)ethyl)amino)pyrido[3,4- d ]

-4-yl)methyl)(methyl)carbamate (35.0 mg, 75.0 µmol, 80.9% yield).

¹ H NMR (400 MHz, CD ₃ OD) δ = 9.43 (br s, 1H), 8.50 (s, 1H), 7.72 (d, J = 7.2 Hz, 1H), 7.52 (dd, J = 1.2, 7.6 Hz , 1H), 7.29-7.24 (m, 1H), 5.68-5.62 (m, 1H), 2.78-2.75 (m, 5H), 1.63 (d, J = 7.2 Hz, 3H), 1.49-1.41 (m, 9H) ), 1.22 (s, 3H).

-4-基)甲基)(甲基)胺甲酸第三丁酯（30.0 mg，64.3 µmol，1.00當量）及((1R ,4R )-2-氧雜-5-氮雜雙環[2.2.1]庚烷（7.01 mg，51.7 µmol，0.8當量，HCl）於DMSO（0.10 mL）中之溶液中添加氟化銫（19.5 mg，128 µmol，4.74 µL，2.00當量）及N,N- 二異丙基乙胺（16.6 mg，128 µmol，22.4 µL，2.00當量），且將混合物在130℃下攪拌1小時。隨後將該溶液冷卻至25℃，倒入水（10.0 mL）中，且將水相用乙酸乙酯（10.0 mL×3）萃取。將合併之有機相用鹽水（10.0 mL×3）洗滌，經無水硫酸鈉乾燥，過濾，且在減壓下濃縮，得到呈黃色固體狀之((7-((1R ,4R )-2-氧雜-5-氮雜雙環[2.2.1]庚-5-基)-1-(((R )-1-(3-氰基-2-甲基苯基)乙基)胺基)吡啶并[3,4-d ]嗒

-4-基)甲基)(甲基)胺甲酸第三丁酯（30.0 mg，粗製）。LCMS [M+1]⁺ : 530.2。Step D: To ( R )-((7-chloro-1-((1-(3-cyano-2-methylphenyl)ethyl)amino)pyrido[3,4- d ]

-4-yl)methyl)(methyl)carbamate (30.0 mg, 64.3 µmol, 1.00 equivalent) and ((1 R ,4 R )-2-oxa-5-azabicyclo[2.2 .1] Heptane (7.01 mg, 51.7 µmol, 0.8 equivalent, HCl) in DMSO (0.10 mL) was added with cesium fluoride (19.5 mg, 128 µmol, 4.74 µL, 2.00 equivalent) and N,N- di Isopropylethylamine (16.6 mg, 128 µmol, 22.4 µL, 2.00 equivalents), and the mixture was stirred at 130°C for 1 hour. Then the solution was cooled to 25°C, poured into water (10.0 mL), and The aqueous phase was extracted with ethyl acetate (10.0 mL×3). The combined organic phase was washed with brine (10.0 mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a yellow solid ((7-((1 R ,4 R )-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-1-((( R )-1-(3-cyano -2-Methylphenyl)ethyl)amino)pyrido[3,4- d ]

-4-yl)methyl)(methyl)carbamic acid tert-butyl ester (30.0 mg, crude). LCMS [M+1] ⁺ : 530.2.

-4-基)甲基)(甲基)胺甲酸第三丁酯（18.0 mg，34.0 µmol，1.00當量）於乙腈（1.50 mL）中之溶液中添加鹽酸/二

烷（0.50 mL），且將混合物在0℃下攪拌30分鐘。隨後將混合物倒入水（5.00 mL）中，且將水相用乙酸乙酯（5.00 mL×3）萃取。將合併之有機相用鹽水（5.00 mL×3）洗滌，經無水硫酸鈉乾燥，過濾，且在減壓下濃縮。將殘餘物藉由製備型HPLC[管柱：3_Phenomenex Luna C18 75×30 mm×3 um；移動相：A相：水（0.05% HCl），B相：乙腈；B%：7%-27%]純化，得到呈黃色固體狀之3-((R )-1-((7-((1R ,4R )-2-氧雜-5-氮雜雙環[2.2.1]庚-5-基)-4-((甲基胺基)甲基)吡啶并[3,4-d ]嗒

-1-基)胺基)乙基)-2-甲基苯甲腈（7.00 mg，14.9 µmol，43.8%產率，99.1%純度，鹽酸鹽）。LCMS [M+1]⁺ : 430.3。Step E: ((7-((1 R ,4 R )-2-oxa-5-azabicyclo[2.2.1]hept-5-yl)-1-((( R )-1-(3 -Cyano-2-methylphenyl)ethyl)amino)pyrido[3,4- d ]

-4-yl)methyl)(methyl)carbamic acid tert-butyl ester (18.0 mg, 34.0 µmol, 1.00 equivalent) in acetonitrile (1.50 mL), add hydrochloric acid/two

Alkane (0.50 mL), and the mixture was stirred at 0 °C for 30 minutes. Then the mixture was poured into water (5.00 mL), and the aqueous phase was extracted with ethyl acetate (5.00 mL×3). The combined organic phase was washed with brine (5.00 mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to preparative HPLC [column: 3_Phenomenex Luna C18 75×30 mm×3 um; mobile phase: phase A: water (0.05% HCl), phase B: acetonitrile; B%: 7%-27%] Purified to obtain 3-(( R )-1-((7-((1 R ,4 R )-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl as a yellow solid )-4-((methylamino)methyl)pyrido[3,4- d ]

-1-yl)amino)ethyl)-2-methylbenzonitrile (7.00 mg, 14.9 µmol, 43.8% yield, 99.1% purity, hydrochloride). LCMS [M+1] ⁺ : 430.3.

-1-基)胺基)乙基)-2-甲基苯甲腈

¹ H NMR (400 MHz, CD ₃ OD) δ = 9.09 (s, 1H), 7.83 (br d, J = 7.6 Hz, 1H), 7.71 (d, J = 7.6 Hz, 1H), 7.63-7.40 (m , 2H), 5.56 (q, J = 6.4 Hz, 1H), 5.41 (br s, 1H), 4.83 (s, 3H), 3.96 (d, J = 6.8 Hz, 1H), 3.84 (br s, 1H) , 3.69 (br d, J = 9.6 Hz, 1H), 3.49 (br d, J = 3.2 Hz, 1H), 2.93 (s, 3H), 2.64 (s, 3H), 2.09 (br s, 2H), 1.84 (d, J = 6.8 Hz, 3H). Example 14-4 3-(( R )-1-((7-((1 R ,4 R )-2-oxa-5-azabicyclo[2.2.1]hept-5-yl)-4- ((Dimethylamino)methyl)pyrido[3,4- d ]

-1-yl)amino)ethyl)-2-methylbenzonitrile

-1-基)胺基)乙基)-2-甲基苯甲腈（12.0 mg，27.9 µmol，1.00當量）及多聚甲醛（1.68 mg）於甲醇（1.00 mL）中之溶液中添加乙酸（168 ug，2.79 µmol，0.16 µL，0.10當量）及氰基硼氫化鈉（3.51 mg，55.9 µmol，2.00當量），且將混合物在25℃攪拌1小時。隨後將混合物倒入水（5.00 mL）中，且將水相用乙酸乙酯（5.00 mL×3）萃取。將合併之有機相用鹽水（5.00 mL×3）洗滌，用無水鈉乾燥，過濾，且在減壓下濃縮。殘餘物藉由製備型HPLC[管柱：3_Phenomenex Luna C18 75×30 mm×3 um；移動相：A相：水（0.05% HCl），B相：乙腈；B%：9%-29%]純化，得到呈黃色固體狀之3-((R )-1-((7-((1R ,4R )-2-氧雜-5-氮雜雙環[2.2.1]庚-5-基)-4-((二甲基胺基)甲基)吡啶并[3,4-d ]嗒

-1-基)胺基)乙基)-2-甲基苯甲腈（5.20 mg，11.4 µmol，40.8%產率，97.2%純度，鹽酸鹽）。LCMS [M+1]⁺ : 444.3。To 3-(( R )-1-((7-((1 R ,4 R )-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-4-((form (Amino)methyl)pyrido[3,4- d ]da

-1-yl)amino)ethyl)-2-methylbenzonitrile (12.0 mg, 27.9 µmol, 1.00 equivalent) and paraformaldehyde (1.68 mg) in methanol (1.00 mL) are added with acetic acid ( 168 ug, 2.79 µmol, 0.16 µL, 0.10 equivalent) and sodium cyanoborohydride (3.51 mg, 55.9 µmol, 2.00 equivalent), and the mixture was stirred at 25°C for 1 hour. Then the mixture was poured into water (5.00 mL), and the aqueous phase was extracted with ethyl acetate (5.00 mL×3). The combined organic phase was washed with brine (5.00 mL×3), dried over anhydrous sodium, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC [column: 3_Phenomenex Luna C18 75×30 mm×3 um; mobile phase: phase A: water (0.05% HCl), phase B: acetonitrile; B%: 9%-29%] , To obtain 3-(( R )-1-((7-((1 R ,4 R )-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl) as a yellow solid -4-((dimethylamino)methyl)pyrido[3,4- d ]

-1-yl)amino)ethyl)-2-methylbenzonitrile (5.20 mg, 11.4 µmol, 40.8% yield, 97.2% purity, hydrochloride). LCMS [M+1] ⁺ : 444.3.

¹ H NMR (400 MHz, CD ₃ OD) δ = 9.11 (s, 1H), 7.83 (br d, J = 7.6 Hz, 1H), 7.71 (d, J = 7.6 Hz, 1H), 7.58-7.29 (m , 2H), 5.56 (q, J = 6.4 Hz, 1H), 5.42 (br s, 1H), 5.04-4.93 (m, 2H), 4.83-4.81 (m, 1H), 3.95 (br d, J = 7.6 Hz, 1H), 3.82 (br s, 1H), 3.67 (br s, 1H), 3.48 (br s, 1H), 3.11 (s, 6H), 2.64 (s, 3H), 2.08 (br s, 2H) , 1.84 (br d, J = 6.8 Hz, 3H).

7-((1R ,4R )-2-氧雜-5-氮雜雙環[2.2.1]庚-5-基)-N -((R )-1-(2-甲基-3-(三氟甲基)苯基)乙基)-4-((甲基胺基)甲基)吡啶并[3,4-d ]嗒

-1-胺 甲酸鹽 ¹ H NMR (400 MHz, CD₃ OD) δ = 8.94 (s, 1H), 8.53 (s, 1H), 7.67 (d,J = 7.6 Hz, 1H), 7.51 (d,J = 7.6 Hz, 1H), 7.25 (t,J = 8.0 Hz, 1H), 7.16 (s, 1H), 5.77 - 5.65 (m, 1H), 5.17 (br s, 1H), 4.81 (s, 1H), 4.57 - 4.43 (m, 2H), 3.99 - 3.92 (m, 1H), 3.85 (d,J = 7.6 Hz, 1H), 3.74 - 3.63 (m, 1H), 3.50 (br d,J = 10.4 Hz, 1H), 2.74 (s, 3H), 2.59 (s, 3H), 2.07 (s, 2H), 1.65 (d,J = 6.8 Hz, 3H)。LCMS [M+1]⁺ : 473.3。 14-6

7-((1R ,4R )-2-氧雜-5-氮雜雙環[2.2.1]庚-5-基)-4-((二甲基胺基)甲基)-N -((R )-1-(2-甲基-3-(三氟甲基)苯基)乙基)吡啶并[3,4-d ]嗒

-1-胺 ¹ H NMR (400 MHz, CD₃ OD) δ = 9.15 (s, 1H), 7.68 (d,J = 8.0 Hz, 1H), 7.50 (d,J = 7.6 Hz, 1H), 7.32 - 7.19 (m, 1H), 7.12 (s, 1H), 5.77 - 5.63 (m, 1H), 5.17 (br s, 1H), 4.80 (s, 1H), 4.07 - 4.01 (m, 1H), 3.99 - 3.93 (m, 2H), 3.85 (d,J = 7.2 Hz, 1H), 3.71 - 3.64 (m, 1H), 3.50 (br d,J = 10.4 Hz, 1H), 2.60 (s, 3H), 2.42 (s, 6H), 2.06 (s, 2H), 1.63 (d,J = 7.2 Hz, 3H)。LCMS [M+1]⁺ : 487.2。 Following the teaching of General Reaction Scheme III and the method of preparing Example 14-3-14-4, the following compounds of formula (I) as shown in Table 14, Examples 14-5 to 14-6 were prepared. Table 14 Example # structure Spectral data 14-5

7-((1 R ,4 R )-2-oxa-5-azabicyclo[2.2.1]hept-5-yl)- N -(( R )-1-(2-methyl-3- (Trifluoromethyl)phenyl)ethyl)-4-((methylamino)methyl)pyrido[3,4- d ]

-1-carbamate ¹ H NMR (400 MHz, CD ₃ OD) δ = 8.94 (s, 1H), 8.53 (s, 1H), 7.67 (d, J = 7.6 Hz, 1H), 7.51 (d, J = 7.6 Hz, 1H) , 7.25 (t, J = 8.0 Hz, 1H), 7.16 (s, 1H), 5.77-5.65 (m, 1H), 5.17 (br s, 1H), 4.81 (s, 1H), 4.57-4.43 (m, 2H), 3.99-3.92 (m, 1H), 3.85 (d, J = 7.6 Hz, 1H), 3.74-3.63 (m, 1H), 3.50 (br d, J = 10.4 Hz, 1H), 2.74 (s, 3H), 2.59 (s, 3H), 2.07 (s, 2H), 1.65 (d, J = 6.8 Hz, 3H). LCMS [M+1] ⁺ : 473.3. 14-6

7-((1 R ,4 R )-2-oxa-5-azabicyclo[2.2.1]hept-5-yl)-4-((dimethylamino)methyl) -N -( ( R )-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)pyrido[3,4- d ]

-1-amine ¹ H NMR (400 MHz, CD ₃ OD) δ = 9.15 (s, 1H), 7.68 (d, J = 8.0 Hz, 1H), 7.50 (d, J = 7.6 Hz, 1H), 7.32-7.19 (m, 1H), 7.12 (s, 1H), 5.77-5.63 (m, 1H), 5.17 (br s, 1H), 4.80 (s, 1H), 4.07-4.01 (m, 1H), 3.99-3.93 (m, 2H ), 3.85 (d, J = 7.2 Hz, 1H), 3.71-3.64 (m, 1H), 3.50 (br d, J = 10.4 Hz, 1H), 2.60 (s, 3H), 2.42 (s, 6H), 2.06 (s, 2H), 1.63 (d, J = 7.2 Hz, 3H). LCMS [M+1] ⁺ : 487.2.

-1-胺

Example 15-1 N -(( R )-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-4-methyl-7-((( S )-tetrahydrofuran-3 -Radical) oxy) 呔

-1-amine

（605 mg，2.35 mmol，1.10當量）於DMSO（1.50 mL）中之溶液中添加氟化鉀（372 mg，6.41 mmol，150 µL，3.00當量）及(R )-1-(3-硝基-5-(三氟甲基)苯基)乙-1-胺（市售，500 mg，2.14 mmol，1.00當量）。將混合物在130℃下攪拌2小時。將反應混合物藉由在20℃下加水（3.00 mL）來淬滅，且隨後用乙酸乙酯（5.00 mL）稀釋且用乙酸乙酯（5.00 mL×3）萃取。將合併之有機層用鹽水（5.00 mL×3）洗滌，經硫酸鈉乾燥，過濾，且在減壓下濃縮，得到殘餘物。將殘餘物藉由製備型TLC（SiO₂ ，石油醚:乙酸乙酯，1:1）純化，得到呈黃色油狀之(R )-7-溴-4-甲基-N -(1-(3-硝基-5-(三氟甲基)苯基)乙基)呔

-1-胺（260 mg，571 µmol，26.8%產率）。LCMS [M+1]⁺ : 455.0。Step A: Add 6-bromo-4-chloro-1-methyl

(605 mg, 2.35 mmol, 1.10 equivalents) potassium fluoride (372 mg, 6.41 mmol, 150 µL, 3.00 equivalents) and ( R )-1-(3-nitro- 5-(Trifluoromethyl)phenyl)ethan-1-amine (commercially available, 500 mg, 2.14 mmol, 1.00 equivalent). The mixture was stirred at 130°C for 2 hours. The reaction mixture was quenched by adding water (3.00 mL) at 20°C, and then diluted with ethyl acetate (5.00 mL) and extracted with ethyl acetate (5.00 mL×3). The combined organic layer was washed with brine (5.00 mL×3), dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by preparative TLC (SiO ₂ , petroleum ether:ethyl acetate, 1:1) to obtain ( R )-7-bromo-4-methyl- N -(1-( 3-nitro-5-(trifluoromethyl)phenyl)ethyl)

-1-amine (260 mg, 571 µmol, 26.8% yield). LCMS [M+1] ⁺ : 455.0.

-1-胺（20.0 mg，43.9 µmol，1.00當量）於二

烷（0.50 mL）及水（0.30 mL）中之溶液中添加氫氧化鉀（4.93 mg，87.9 µmol，2.00當量）及t -BuXPhos Pd G3（3.49 mg，4.39 µmol，0.10當量）。將混合物在80℃下攪拌2小時。將混合物用水（3.00 mL）稀釋且用乙酸乙酯（3.00 mL×2）萃取。將合併之有機層用鹽水（3.00 mL×3）洗滌，經硫酸鈉乾燥，過濾，且在減壓下濃縮，得到呈褐色油狀之粗產物(R )-1-甲基-4-((1-(3-硝基-5-(三氟甲基)苯基)乙基)胺基)呔

-6-醇（16.0 mg，40.8 umol），其無需進一步純化即可用於下一步。LCMS [M+1]⁺ : 393.1。Step B: To ( R )-7-bromo-4-methyl- N -(1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)

-1-amine (20.0 mg, 43.9 µmol, 1.00 equivalent) in two

Potassium hydroxide (4.93 mg, 87.9 µmol, 2.00 equivalent) and t- BuXPhos Pd G3 (3.49 mg, 4.39 µmol, 0.10 equivalent) were added to a solution in alkane (0.50 mL) and water (0.30 mL). The mixture was stirred at 80°C for 2 hours. The mixture was diluted with water (3.00 mL) and extracted with ethyl acetate (3.00 mL×2). The combined organic layer was washed with brine (3.00 mL×3), dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product ( R )-1-methyl-4-(( 1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)

-6-alcohol (16.0 mg, 40.8 umol), which can be used in the next step without further purification. LCMS [M+1] ⁺ : 393.1.

-6-醇（16.0 mg，40.8 µmol，1.00當量）於DMF（1.50 mL）中之溶液中添加碳酸銫（39.9 mg，122 µmol，3.00當量）及(R )-四氫呋喃-3-基4-甲基苯磺酸鹽（14.8 mg，61.2 µmol，1.50當量）。將混合物在80℃下攪拌12小時。將殘餘物用水（2.00 mL）稀釋且用乙酸乙酯（3.00 mL×3）萃取。將合併之有機層用鹽水（5.00 mL×2）洗滌，經硫酸鈉乾燥，過濾，且在減壓下濃縮，得到殘餘物。粗產物4-甲基-N -((R )-1-(3-硝基-5-(三氟甲基)苯基)乙基)-7-(((S )-四氫呋喃-3-基)氧基)呔

-1-胺（18.0 mg，38.93 µmol，粗製）呈褐色油狀，其無需進一步純化即可用於下一步。LCMS [M+1]⁺ : 463.1。Step C: To ( R )-1-methyl-4-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)

-6-Alcohol (16.0 mg, 40.8 µmol, 1.00 equivalent) in DMF (1.50 mL) was added with cesium carbonate (39.9 mg, 122 µmol, 3.00 equivalent) and ( R )-tetrahydrofuran-3-yl 4-methyl Benzenesulfonate (14.8 mg, 61.2 µmol, 1.50 equivalents). The mixture was stirred at 80°C for 12 hours. The residue was diluted with water (2.00 mL) and extracted with ethyl acetate (3.00 mL×3). The combined organic layer was washed with brine (5.00 mL×2), dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. Crude product 4-methyl- N -(( R )-1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)-7-((( S )-tetrahydrofuran-3-yl )Oxy)

-1-amine (18.0 mg, 38.93 µmol, crude) is a brown oil, which can be used in the next step without further purification. LCMS [M+1] ⁺ : 463.1.

-1-胺（18.0 mg，38.9 µmol，1.00當量）於乙醇（1.00 mL）及水（0.20 mL）中之溶液中添加鐵粉（10.9 mg，195 µmol，5.00當量）及氯化銨（10.4 mg，195 µmol，5.00當量）。將混合物在80℃下攪拌2小時。將殘餘物用甲醇（3.00 mL）稀釋，過濾，且在減壓下濃縮，得到殘餘物。將殘餘物藉由製備型HPLC[Phenomenex Gemini-NX C18 75×30 mm×3 um；移動相：A相：水（10 mM NH₄ HCO₃ ），B相：MeCN；B%：25%-55%]純化，得到呈灰白色固體狀之N -((R )-1-(3-胺基-5-(三氟甲基)苯基)乙基)-4-甲基-7-(((S )-四氫呋喃-3-基)氧基)呔

-1-胺（7.00 mg，16.2 µmol，41.6%產率）。LCMS [M+1]⁺ : 433.2。Step D: To -methyl- N -(( R )-1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)-7-((( S )-tetrahydrofuran-3- (Base) oxy) 呔

-1-amine (18.0 mg, 38.9 µmol, 1.00 equivalent) in ethanol (1.00 mL) and water (0.20 mL) with iron powder (10.9 mg, 195 µmol, 5.00 equivalent) and ammonium chloride (10.4 mg) , 195 µmol, 5.00 equivalent). The mixture was stirred at 80°C for 2 hours. The residue was diluted with methanol (3.00 mL), filtered, and concentrated under reduced pressure to give a residue. The residue was subjected to preparative HPLC [Phenomenex Gemini-NX C18 75×30 mm×3 um; mobile phase: phase A: water (10 mM NH ₄ HCO ₃ ), phase B: MeCN; B%: 25%-55 %] was purified to obtain N -(( R )-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-4-methyl-7-((( S )-tetrahydrofuran-3-yl)oxy) 呔

-1-amine (7.00 mg, 16.2 µmol, 41.6% yield). LCMS [M+1] ⁺ : 433.2.

¹ H NMR (400 MHz, CD ₃ OD) δ = 8.00 (d, J = 8.8 Hz, 1H), 7.77 (d, J = 2.4 Hz, 1H), 7.49 (dd, J = 2.4, 9.2 Hz, 1H) , 6.98 (br d, J = 2.4 Hz, 2H), 6.76 (s, 1H), 5.42 (q, J = 6.8 Hz, 1H), 5.34 (br dd, J = 4.4, 6.0 Hz, 1H), 4.13- 3.90 (m, 4H), 2.67 (s, 3H), 2.46-2.32 (m, 1H), 2.26-2.15 (m, 1H), 1.64 (d, J = 7.2 Hz, 3H). Example 15-2

（259 mg，1.01 mmol，1.00當量）於二甲基亞碸（3.00 mL）、N,N- 二異丙基乙胺（390 mg，3.02 mmol，526 µL，3.00當量）及氟化鉀（175 mg，3.02 mmol，70.7 µL，3.00當量）中之溶液在氮氣氛圍下在130℃下於密封管中攪拌12小時。將反應冷卻至25℃，且用水（50.0 mL）淬滅反應，且隨後用乙酸乙酯（30.0 mL×3）萃取。將合併之有機相用鹽水（20.0 mL）洗滌，經無水硫酸鈉乾燥，過濾，且在減壓下濃縮，得到殘餘物。將殘餘物藉由製備型TLC（SiO₂ ，石油醚/乙酸乙酯＝0/1）純化，得到呈黃色固體狀之(R )-7-溴-4-甲基-N-(1-(2-甲基-5-硝基-3-(三氟甲基)苯基)乙基)呔

-1-胺（200 mg，426 µmol，42.3%產率）。LCMS [M+1]⁺ : 469.0。Step A: Combine ( R )-1-(2-methyl-5-nitro-3-(trifluoromethyl)phenyl)ethan-1-amine (250 mg, 1.01 mmol, 1.00 equivalent) and 6- Bromo-4-chloro-1-methyl

(259 mg, 1.01 mmol, 1.00 equivalent) in dimethyl sulfide (3.00 mL), N,N -diisopropylethylamine (390 mg, 3.02 mmol, 526 µL, 3.00 equivalent) and potassium fluoride (175 The solution in mg, 3.02 mmol, 70.7 µL, 3.00 equivalents) was stirred in a sealed tube at 130°C for 12 hours under a nitrogen atmosphere. The reaction was cooled to 25°C, and quenched with water (50.0 mL), and then extracted with ethyl acetate (30.0 mL×3). The combined organic phase was washed with brine (20.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by preparative TLC (SiO ₂ , petroleum ether/ethyl acetate=0/1) to obtain ( R )-7-bromo-4-methyl-N-(1-( 2-methyl-5-nitro-3-(trifluoromethyl)phenyl)ethyl)

-1-amine (200 mg, 426 µmol, 42.3% yield). LCMS [M+1] ⁺ : 469.0.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 8.81 (s, 1H), 8.80 (s, 1H), 8.25 (s, 1H), 8.07-8.04 (m, 1H), 7.96-7.92 (m, 2H), 5.68-5.64 (m, 1H), 2.74 (s, 3H), 2.60 (s, 3H), 1.58 (d, J = 6.8 Hz, 3H).

啉（44.5 mg，511 µmol，45.0 µL，3.00當量）、(R )-7-溴-4-甲基-N-(1-(2-甲基-5-硝基-3-(三氟甲基)苯基)乙基)呔

-1-胺（80.0 mg，170 µmol，1.00當量）及碳酸銫（166 mg，511 µmol，3.00當量）於二

烷（2.00 mL）中之溶液中添加RuPhos（15.9 mg，34.1 µmol，0.20當量）及Pd₂ (dba)₃ （15.6 mg，17.0 µmol，0.10當量）。將混合物在110℃下攪拌1小時，隨後冷卻至25℃，用水（40.0 mL）淬滅，且隨後用乙酸乙酯（20.0 mL×3）萃取。將合併之有機相用鹽水（40.0 mL）洗滌，經無水硫酸鈉乾燥，過濾，且在減壓下濃縮，得到殘餘物。將殘餘物藉由製備型TLC（SiO₂ ，二氯甲烷:甲醇＝10/1）純化，得到呈黃色固體狀之(R )-4-甲基-N -(1-(2-甲基-5-硝基-3-(三氟甲基)苯基)乙基)-7-

啉基呔

-1-胺（50.0 mg，105 µmol，61.6%產率）。Step B: To

Morpholine (44.5 mg, 511 µmol, 45.0 µL, 3.00 equivalents), ( R )-7-bromo-4-methyl-N-(1-(2-methyl-5-nitro-3-(trifluoromethyl) (Phenyl) Ethyl) Ethyl)

-1-amine (80.0 mg, 170 µmol, 1.00 equivalent) and cesium carbonate (166 mg, 511 µmol, 3.00 equivalent) in two

Add RuPhos (15.9 mg, 34.1 µmol, 0.20 equivalent) and Pd ₂ (dba) ₃ (15.6 mg, 17.0 µmol, 0.10 equivalent) to the solution in alkane (2.00 mL). The mixture was stirred at 110°C for 1 hour, then cooled to 25°C, quenched with water (40.0 mL), and then extracted with ethyl acetate (20.0 mL×3). The combined organic phase was washed with brine (40.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by preparative TLC (SiO ₂ , dichloromethane: methanol = 10/1) to obtain ( R )-4-methyl- N -(1-(2-methyl- 5-nitro-3-(trifluoromethyl)phenyl)ethyl)-7-

Linyl

-1-amine (50.0 mg, 105 µmol, 61.6% yield).

¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 8.57 (d, J = 2.4 Hz, 1H), 8.24 (d, J = 2.4 Hz, 1H), 7.82 (d, J = 8.8 Hz, 1H), 7.62-7.58 (m, 2H), 5.67-5.64 (m, 1H), 3.85-3.82 (m, 4H), 3.44-3.43 (m, 4H), 2.74 (s, 3H), 2.51 (s, 3H), 1.59 (d, J = 7.2 Hz, 3H).

啉基呔

-1-胺（45.0 mg，94.6 µmol，1.00當量）及氯化銨（(50.6 mg，946 µmol，10.0當量）於乙醇（1.20 mL）及水（0.40 mL）中之溶液添加鐵粉（52.8 mg，946.4 µmol，10.0當量）。將反應混合物在90℃下攪拌1小時，隨後冷卻至25℃。將混合物過濾且在減壓下濃縮，得到殘餘物，將其藉由製備型HPLC[管柱：Phenomenex luna C18 80×40 mm×3 um；移動相：A相：水（0.04% HCl），B相：乙腈；B%：12%-38%]純化，得到呈白色固體狀之(R )-N -(1-(5-胺基-2-甲基-3-(三氟甲基)苯基)乙基)-4-甲基-7-

啉基呔

-1-胺（20.0 mg，44.8 µmol，47.3%產率，鹽酸鹽）。LCMS [M+1]⁺ : 446.1。Step C: Under a nitrogen atmosphere at 90°C, add ( R )-4-methyl- N -(1-(2-methyl-5-nitro-3-(trifluoromethyl)phenyl)ethyl Base)-7-

Linyl

A solution of -1-amine (45.0 mg, 94.6 µmol, 1.00 equivalent) and ammonium chloride ((50.6 mg, 946 µmol, 10.0 equivalent) in ethanol (1.20 mL) and water (0.40 mL) is added with iron powder (52.8 mg) , 946.4 µmol, 10.0 equivalents). The reaction mixture was stirred at 90°C for 1 hour and then cooled to 25°C. The mixture was filtered and concentrated under reduced pressure to obtain a residue, which was subjected to preparative HPLC [column: Phenomenex luna C18 80×40 mm×3 um; mobile phase: phase A: water (0.04% HCl), phase B: acetonitrile; B%: 12%-38%] Purified to obtain a white solid ( R )- N -(1-(5-amino-2-methyl-3-(trifluoromethyl)phenyl)ethyl)-4-methyl-7-

Linyl

-1-amine (20.0 mg, 44.8 µmol, 47.3% yield, hydrochloride). LCMS [M+1] ⁺ : 446.1.

¹ H NMR (400MHz, DMSO- d ₆ ) δ = 14.85 (s, 1H), 8.62 (s, 1H), 8.16 (d, J = 9.2 Hz, 1H), 7.93 (s, 1H), 7.77-7.74 ( m, 1H), 7.23-7.22 (m, 1H), 7.08 (s, 1H), 5.37-5.34 (m, 1H), 3.83-3.81 (m, 4H), 3.70-3.68 (m, 4H), 2.73 ( s, 3H), 2.43 (s, 3H), 1.59 (d, J = 6.8 Hz, 3H).

SFC conditions: Chiralcel OD-3 3µm, 0.46 cm inner diameter×5 cm L; mobile phase: A is SFC CO ₂ and B is MeOH (0.05% isopropylamine); gradient: B in A increases from 10% within 3 minutes To 40%; flow rate: 4.0 ml/min; column temperature: 35°C; wavelength: 220 nm; system back pressure: 100 bar.

N -((R )-1-(5-胺基-2-甲基-3-(三氟甲基)苯基)乙基)-4-甲基-7-(((S )-四氫呋喃-3-基)氧基)呔

-1-胺 鹽酸鹽 ¹ H NMR (400MHz, CD₃ OD) δ = 8.37 - 8.35 (m, 1H), 8.26 (d,J = 2.4 Hz, 1H), 7.79 (s, 1H), 7.75 - 7.72 (m, 1H), 7.47 - 7.46 (m, 1H), 5.58 - 5.54 (m, 2H), 4.15 - 4.12 (m, 1H), 4.05 - 4.03 (m, 2H), 3.99 - 3.96 (m, 1H), 2.85 (s, 3H), 2.66 (s, 3H), 2.52 - 2.48 (m, 1H), 2.25 - 2.25 (m, 1H), 1.73 (d,J = 7.2 Hz, 3H)。LCMS [M+1]⁺ : 447.1。 實例16-1 (R )-N -(1-(4-胺基-6-(三氟甲基)吡啶-2-基)乙基)-4-甲基-7-

啉基呔

-1-胺

Following the teaching of General Reaction Scheme VI and the method of preparing Examples 15-1-15-2, the following compounds of formula (I), Example 15-3, as shown in Table 15 were prepared. Table 15 Example # structure Spectral data 15-3

N -(( R )-1-(5-amino-2-methyl-3-(trifluoromethyl)phenyl)ethyl)-4-methyl-7-((( S )-tetrahydrofuran- 3-yl)oxy)

-1-amine hydrochloride ¹ H NMR (400MHz, CD ₃ OD) δ = 8.37-8.35 (m, 1H), 8.26 (d, J = 2.4 Hz, 1H), 7.79 (s, 1H), 7.75-7.72 (m, 1H), 7.47 -7.46 (m, 1H), 5.58-5.54 (m, 2H), 4.15-4.12 (m, 1H), 4.05-4.03 (m, 2H), 3.99-3.96 (m, 1H), 2.85 (s, 3H) , 2.66 (s, 3H), 2.52-2.48 (m, 1H), 2.25-2.25 (m, 1H), 1.73 (d, J = 7.2 Hz, 3H). LCMS [M+1] ⁺ : 447.1. Example 16-1 ( R ) -N -(1-(4-amino-6-(trifluoromethyl)pyridin-2-yl)ethyl)-4-methyl-7-

Linyl

-1-amine

（7.03 g，27.3 mmol，1.10當量）及N,N- 二異丙基乙胺（12.8 g，99.3 mmol，17.3 mL，4.00當量）於DMSO（1.00 mL）中之溶液中添加氟化銫（5.66 g，37.3 mmol，1.37 mL，1.50當量），且將混合物在氮氣氛圍下在130℃下攪拌2小時。隨後將混合物冷卻至25℃，用乙酸乙酯（300 mL）稀釋，用鹽水（200 mL×2）洗滌，經無水硫酸鈉乾燥，過濾，且在減壓下濃縮，得到殘餘物，將殘餘物藉由矽膠層析法（石油醚/乙酸乙酯=10/1至二氯甲烷/甲醇=10/1）純化，得到呈褐色固體狀之(R )-N -(1-(4-胺基-6-(三氟甲基)吡啶-2-基)乙基)-7-溴-4-甲基呔

-1-胺（9.00 g，21.1 mmol，85.0%產率）。Step A: To ( R )-2-(1-aminoethyl)-6-(trifluoromethyl)pyridine-4-amine (6.00 g, 24.8 mmol, 1.00 equivalent, hydrochloride), 6-bromo -4-Chloro-1-methyl

(7.03 g, 27.3 mmol, 1.10 equiv) and N, N- diisopropylethylamine (12.8 g, 99.3 mmol, 17.3 mL, 4.00 equiv.) In DMSO was added (1.00 mL) in a solution of cesium fluoride (5.66 g, 37.3 mmol, 1.37 mL, 1.50 equivalents), and the mixture was stirred at 130°C for 2 hours under a nitrogen atmosphere. The mixture was then cooled to 25°C, diluted with ethyl acetate (300 mL), washed with brine (200 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. Purified by silica gel chromatography (petroleum ether/ethyl acetate=10/1 to dichloromethane/methanol=10/1), ( R ) -N -(1-(4-amino group) was obtained as a brown solid -6-(Trifluoromethyl)pyridin-2-yl)ethyl)-7-bromo-4-methyl

-1-amine (9.00 g, 21.1 mmol, 85.0% yield).

¹ H NMR (400 MHz,CDCl ₃ ) δ = 8.11 (d, J = 2.0 Hz, 1H), 7.89 (dd, J = 1.6, 8.8 Hz, 1H), 7.78 (d, J = 8.8 Hz, 1H), 6.94 (d, J = 1.6 Hz, 1H), 6.87 (br s, 1H), 6.80 (d, J = 2.0 Hz, 1H), 5.58-5.49 (m, 1H), 4.89 (br s, 2H), 2.77 (s, 3H), 1.68 (d, J = 6.4 Hz, 3H).

-1-胺（10.0 g，23.5 mmol，1.00當量）及DMAP（287 mg，2.35 mmol，0.10當量）於THF（100 mL）中之溶液中添加二碳酸二第三丁酯（10.5 g，48.1 mmol，11.1 mL，2.05當量），將反應混合物在40℃攪拌30分鐘，隨後在減壓下濃縮，得到殘餘物。將殘餘物藉由矽膠層析法（石油醚/乙酸乙酯＝10/1至1/1）純化，得到呈褐色固體狀之(R )-(2-(1-((7-溴-4-甲基呔

-1-基)胺基)乙基)-6-(三氟甲基)吡啶-4-基)(第三丁氧基羰基)胺甲酸第三丁酯（7.45 g，11.9 mmol，50.7%產率）。LCMS [M+3]⁺ : 628.0。Step B: To ( R ) -N -(1-(4-amino-6-(trifluoromethyl)pyridin-2-yl)ethyl)-7-bromo-4-methyl

A solution of -1-amine (10.0 g, 23.5 mmol, 1.00 equivalent) and DMAP (287 mg, 2.35 mmol, 0.10 equivalent) in THF (100 mL) was added with di-tert-butyl dicarbonate (10.5 g, 48.1 mmol) , 11.1 mL, 2.05 equivalents), the reaction mixture was stirred at 40°C for 30 minutes, and then concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel chromatography (petroleum ether/ethyl acetate = 10/1 to 1/1) to obtain ( R )-(2-(1-((7-bromo-4) as a brown solid -Methyl

-1-yl)amino)ethyl)-6-(trifluoromethyl)pyridin-4-yl)(tert-butoxycarbonyl)carbamate (7.45 g, 11.9 mmol, 50.7% yield Rate). LCMS [M+3] ⁺ : 628.0.

啉（4.09 g，46.9 mmol，4.13 mL，4.00當量）及(R )-(2-(1-((7-溴-4-甲基呔

-1-基)胺基)乙基)-6-(三氟甲基)吡啶-4-基)(第三丁氧基羰基)胺甲酸第三丁酯（7.35 g，11.7 mmol，1.00當量）於二

烷（100 mL）中之溶液中添加Pd₂ (dba)₃ （1.07 g，1.17 mmol，0.10當量）、RuPhos（1.09 g，2.35 mmol，0.20當量）及碳酸銫（11.5 g，35.2 mmol，3.00當量），且將反應混合物在105℃下攪拌1小時。將反應混合物冷卻至25℃，過濾，且將濾餅用甲醇（200 mL）洗滌。在減壓下濃縮濾液，得到殘餘物，將其藉由矽膠層析法（石油醚/乙酸乙酯＝10/1至DCM/甲醇＝10/1）純化，得到呈褐色固體狀之(R )-(2-(1-((4-甲基-7-

啉基呔

-1-基)胺基)乙基)-6-(三氟甲基)吡啶-4-基)胺甲酸第三丁酯（4.75 g，8.92 mmol，76.0%產率）。LCMS [M+1]⁺ : 433.3。Step C: Under nitrogen,

Morinoline (4.09 g, 46.9 mmol, 4.13 mL, 4.00 equivalents) and ( R )-(2-(1-((7-bromo-4-methyl

-1-yl)amino)ethyl)-6-(trifluoromethyl)pyridin-4-yl)(tert-butoxycarbonyl)carbamate (7.35 g, 11.7 mmol, 1.00 equivalent) Yuji

_{Add Pd 2} (dba) ₃ (1.07 g, 1.17 mmol, 0.10 equivalent), RuPhos (1.09 g, 2.35 mmol, 0.20 equivalent) and cesium carbonate (11.5 g, 35.2 mmol, 3.00 equivalent) to the solution in alkane (100 mL) ), and the reaction mixture was stirred at 105°C for 1 hour. The reaction mixture was cooled to 25°C, filtered, and the filter cake was washed with methanol (200 mL). The filtrate was concentrated under reduced pressure to obtain a residue, which was purified by silica gel chromatography (petroleum ether/ethyl acetate=10/1 to DCM/methanol=10/1) to obtain ( R ) as a brown solid -(2-(1-((4-methyl-7-

Linyl

-1-yl)amino)ethyl)-6-(trifluoromethyl)pyridin-4-yl)carbamate (4.75 g, 8.92 mmol, 76.0% yield). LCMS [M+1] ⁺ : 433.3.

啉基呔

-1-基)胺基)乙基)-6-(三氟甲基)吡啶-4-基)胺甲酸第三丁酯（4.75 g，8.92 mmol，1.00當量）於乙腈（20.0 mL）中之溶液中添加HCl/二

烷（20.0 mL），將反應在0-25℃下攪拌3小時。此後，將混合物藉由分批添加固體碳酸氫鈉將pH調節至pH＝7。將所得之混合物在減壓下濃縮，得到殘餘物，將其用水（200 mL）濕磨，隨後過濾。用水（30.0 mL×3）洗滌濾餅，收集，且進一步用乙腈（100 mL）濕磨。將所得之懸浮液過濾，且將濾餅收集且真空乾燥，得到呈灰白色固體狀之產物(R )-N -(1-(4-胺基-6-(三氟甲基)吡啶-2-基)乙基)-4-甲基-7-

啉基呔

-1-胺（3.64 g，7.99 mmol，89.6%產率，94.9%純度）。LCMS [M+1]⁺ : 433.1。Step D: At 0 ℃, to ( R )-(2-(1-((4-methyl-7-

Linyl

-1-yl)amino)ethyl)-6-(trifluoromethyl)pyridin-4-yl)carbamate (4.75 g, 8.92 mmol, 1.00 equivalent) in acetonitrile (20.0 mL) Add HCl/two to the solution

Alkane (20.0 mL), and the reaction was stirred at 0-25°C for 3 hours. Thereafter, the mixture was adjusted to pH=7 by adding solid sodium bicarbonate in batches. The resulting mixture was concentrated under reduced pressure to obtain a residue, which was wet-milled with water (200 mL) and then filtered. The filter cake was washed with water (30.0 mL×3), collected, and further wet-milled with acetonitrile (100 mL). The resulting suspension was filtered, and the filter cake was collected and dried in vacuo to obtain the product ( R ) -N -(1-(4-amino-6-(trifluoromethyl)pyridine-2-) as an off-white solid (Yl)ethyl)-4-methyl-7-

Linyl

-1-amine (3.64 g, 7.99 mmol, 89.6% yield, 94.9% purity). LCMS [M+1] ⁺ : 433.1.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 7.84 (d, J = 9.2 Hz, 1H), 7.64 (d, J = 2.0 Hz, 1H), 7.59 (dd, J = 2.0, 8.8 Hz, 1H ), 7.28 (d, J = 6.8 Hz, 1H), 6.73 (d, J = 2.0 Hz, 1H), 6.65 (d, J = 1.6 Hz, 1H), 6.40 (s, 2H), 5.32-5.23 (m , 1H), 3.82 (t, J = 4.8 Hz, 4H), 3.44-3.39 (m, 4H), 2.56 (s, 3H), 1.57 (d, J = 7.2 Hz, 3H). Example 16-2

（4.87 g，22.8 mmol，1.10當量）及(R )-2-(1-胺基乙基)-6-(三氟甲基)吡啶-4-胺（5.00 g，20.7 mmol，1.00當量，鹽酸鹽）於DMSO（40.0 mL）中之溶液中添加氟化銫（9.43 g，62.1 mmol，2.29 mL，3.00當量）及N,N- 二異丙基乙胺（8.02 g，62.1 mmol，10.8 mL，3.00當量），且將混合物在130℃下攪拌2小時。在此時間後，將混合物倒入水（50.0 mL）中，且用乙酸乙酯（150 mL×3）萃取。將合併之有機相用鹽水（150 mL×3）洗滌，經無水硫酸鈉乾燥，過濾，且在減壓下濃縮。將殘餘物用石油醚:乙酸乙酯＝1:1洗滌，得到呈灰色固體狀之(R )-N -(1-(4-胺基-6-(三氟甲基)吡啶-2-基)乙基)-7-氯-4-甲基吡啶并[3,4-d ]嗒

-1-胺（5.00 g，13.1 mmol，63.1%產率）。LCMS [M+1]⁺ : 383.2。Step A: To 1,7-dichloro-4-methylpyrido[3,4- d ]

(4.87 g, 22.8 mmol, 1.10 equivalents) and ( R )-2-(1-aminoethyl)-6-(trifluoromethyl)pyridine-4-amine (5.00 g, 20.7 mmol, 1.00 equivalents, salt Salt) in DMSO (40.0 mL) was added cesium fluoride (9.43 g, 62.1 mmol, 2.29 mL, 3.00 equivalents) and N,N -diisopropylethylamine (8.02 g, 62.1 mmol, 10.8 mL) , 3.00 equivalents), and the mixture was stirred at 130°C for 2 hours. After this time, the mixture was poured into water (50.0 mL), and extracted with ethyl acetate (150 mL×3). The combined organic phase was washed with brine (150 mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was washed with petroleum ether: ethyl acetate=1:1 to obtain ( R ) -N -(1-(4-amino-6-(trifluoromethyl)pyridin-2-yl) as a gray solid )Ethyl)-7-chloro-4-methylpyrido[3,4- d ]

-1-amine (5.00 g, 13.1 mmol, 63.1% yield). LCMS [M+1] ⁺ : 383.2.

-1-胺（115 mg，300 µmol，1.00當量）及(1R,4R)-2-氧雜-5-氮雜雙環[2.2.1]庚烷（61.1 mg，451 µmol，1.50當量，鹽酸鹽）於DMSO（0.20 mL）中之溶液中添加N,N- 二異丙基乙胺（77.7 mg，601 µmol，105 μL，2.00當量）及氟化銫（274 mg，1.80 mmol，66.5 μL，6.00當量），且將混合物在130℃下攪拌2小時。將混合物用水（10.0 mL）稀釋，且用乙酸乙酯（10.0 mL×3）萃取，且將合併之有機層用鹽水（20.0 mL×3）洗滌，經硫酸鈉乾燥，過濾，且在減壓下濃縮。將殘餘物藉由製備型HPLC[管柱：3_Phenomenex Luna C18 75×30 mm×3 μm；移動相：A相：水（0.05% HCl），B相：乙腈；B%：14%-34%]純化，得到呈黃色固體狀之N -((R )-1-(4-胺基-6-(三氟甲基)吡啶-2-基)乙基)-7-((1R ,4R )-2-氧雜-5-氮雜雙環[2.2.1]庚-5-基)-4-甲基吡啶并[3,4-d ]嗒

-1-胺（93.9 mg，211 µmol，70.2%產率）。LCMS [M+1]⁺ : 446.2。Step B: To ( R ) -N -(1-(4-amino-6-(trifluoromethyl)pyridin-2-yl)ethyl)-7-chloro-4-methylpyrido[3, 4- d ]

-1-amine (115 mg, 300 µmol, 1.00 equivalent) and (1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane (61.1 mg, 451 µmol, 1.50 equivalent, hydrochloric acid Salt) in DMSO (0.20 mL), add N,N -diisopropylethylamine (77.7 mg, 601 µmol, 105 μL, 2.00 equivalent) and cesium fluoride (274 mg, 1.80 mmol, 66.5 μL). 6.00 equivalents), and the mixture was stirred at 130°C for 2 hours. The mixture was diluted with water (10.0 mL) and extracted with ethyl acetate (10.0 mL×3), and the combined organic layer was washed with brine (20.0 mL×3), dried over sodium sulfate, filtered, and under reduced pressure concentrate. The residue was subjected to preparative HPLC [column: 3_Phenomenex Luna C18 75×30 mm×3 μm; mobile phase: phase A: water (0.05% HCl), phase B: acetonitrile; B%: 14%-34%] Purified to obtain N -(( R )-1-(4-amino-6-(trifluoromethyl)pyridin-2-yl)ethyl)-7-((1 R ,4 R ) as a yellow solid )-2-oxa-5-azabicyclo[2.2.1]hept-5-yl)-4-methylpyrido[3,4- d ]

-1-amine (93.9 mg, 211 µmol, 70.2% yield). LCMS [M+1] ⁺ : 446.2.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 15.19-14.58 (m, 1H), 9.29 (s, 1H), 8.92-8.62 (m, 1H), 8.12-7.37 (m, 1H), 6.83 ( d, J = 2.0 Hz, 1H), 6.71 (br s, 1H), 5.41-5.18 (m, 1H), 5.15-5.03 (m, 1H), 4.94-4.76 (m, 1H), 4.02-3.81 (m , 2H), 3.80-3.65 (m, 3H), 2.05 (br d, J = 4.8 Hz, 2H), 1.65 (br d, J = 6.4 Hz, 3H).

¹ H NMR (400 MHz, CD ₃ OD) δ = 9.29 (s, 1H), 7.80-7.22 (m, 1H), 7.12 (d, J = 2.0 Hz, 1H), 7.05 (br s, 1H), 5.53 (br s, 1H), 5.21 (q, J = 6.4 Hz, 1H), 5.17-4.97 (m, 1H), 4.11-3.83 (m, 2H), 3.82-3.55 (m, 2H), 2.85 (s, 3H), 2.24-2.05 (m, 2H), 1.80 (br d, J = 6.8 Hz, 3H).

(R )-N -(1-(4-胺基-6-(三氟甲基)吡啶-2-基)乙基)-4-甲基-7-

啉基吡啶并[3,4-d ]嗒

-1-胺 ¹ H NMR (400 MHz, CD₃ OD) δ 9.03 (s, 1H), 7.27 (s, 1H), 6.79 - 6.72 (m, 2H), 5.29 (q,J = 6.8 Hz, 1H), 3.86 - 3.79 (m, 4H), 3.75 - 3.70 (m, 4H), 1.63 (d,J = 6.8 Hz, 3H)。LCMS [M+1]⁺ : 434.2。 16-4

N -((R )-1-(4-胺基-6-(三氟甲基)吡啶-2-基)乙基)-7-(6-氧雜-3-氮雜雙環[3.1.1]庚-3-基)-4-甲基呔

-1-胺 ¹ H NMR (400 MHz, CD₃ OD) δ = 7.97 (d,J = 9.2 Hz, 1H), 7.48 (dd,J = 2.4, 9.2 Hz, 1H), 7.30 (d,J = 2.4 Hz, 1H), 6.78 (q,J =2.0 Hz, 2H), 5.34 (q,J = 6.8 Hz, 1H), 4.90 - 4.87 (m, 2H), 3.87 - 3.78 (m, 2H), 3.76 - 3.68 (m, 2H), 3.35 (s, 1H), 2.65 (s, 3H), 2.06 (d,J = 9.2 Hz, 1H), 1.64 (d,J = 6.8 Hz, 3H)。LCMS [M+1]⁺ : 445.2。 16-5

N -((R )-1-(4-胺基-6-(三氟甲基)吡啶-2-基)乙基)-4-甲基-7-((1R ,4R )-5-甲基-2,5-二氮雜雙環[2.2.2]辛-2-基)呔

-1-胺 鹽酸鹽 ¹ H NMR (400 MHz, CD₃ OD) δ = 8.30 (d,J = 9.2 Hz, 1H), 7.87 (br s, 1H), 7.66 (br d,J = 9.2 Hz, 1H), 7.25 (br s, 1H), 7.17 (s, 1H), 5.46 - 5.18 (m, 1H), 4.98 - 4.94 (m, 1H), 4.45 - 4.19 (m, 1H), 4.16 - 3.83 (m, 3H), 3.56 - 3.36 (m, 1H), 3.11 (s, 3H), 2.85 (s, 3H), 2.62 - 2.38 (m, 1H), 2.36 - 2.04 (m, 3H), 1.87 (br d,J = 7.2 Hz, 3H)。LCMS [M+1]⁺ : 472.2。 16-6

N -((R )-1-(4-胺基-6-(三氟甲基)吡啶-2-基)乙基)-4-甲基-7-((1R ,4R )-5-甲基-2,5-二氮雜雙環[2.2.2]辛-2-基)吡啶并[3,4-d ]嗒

-1-胺 鹽酸鹽 ¹ H NMR (400 MHz, CD₃ OD δ = 9.37 (s, 1H), 8.18 - 7.44 (m, 1H), 7.31 - 7.23 (m, 1H), 7.19 (d,J = 2.0 Hz, 1H), 5.69 - 5.39 (m, 1H), 5.29 (br dd,J = 5.2, 6.8 Hz, 1H), 4.36 (br d,J = 13.6 Hz, 1H), 4.06 (br d,J = 11.6 Hz, 3H), 3.53 - 3.36 (m, 1H), 3.11 (s, 3H), 2.89 (s, 3H), 2.61 - 2.38 (m, 1H), 2.06 - 2.30 (m, 3H), 1.87 (br dd,J = 2.4, 6.8 Hz, 3H)。LCMS [M+1]⁺ : 473.2。 16-7

(R )-2-(1-((1-(4-胺基-6-(三氟甲基)吡啶-2-基)乙基)胺基)-4-甲基吡啶并[3,4-d ]嗒

-7-基)-6-甲基-2,6-二氮雜螺[3.4]辛-5-酮 鹽酸鹽 ¹ H NMR (400 MHz, CD₃ OD) δ = 9.22 (s, 1H), 7.34 (s, 1H), 7.09 (d,J = 2.0 Hz, 1H), 7.04 (br s, 1H), 5.20 (q,J = 7.2 Hz, 1H), 4.48 (dd,J = 3.6, 9.6 Hz, 2H), 4.30 (br t,J = 9.6 Hz, 2H), 3.49 (t,J = 6.8 Hz, 2H), 2.93 (s, 3H), 2.83 (s, 3H), 2.55 (t,J = 6.8 Hz, 2H), 1.78 (d,J = 6.8 Hz, 3H)。LCMS [M+1]⁺ : 487.2。 16-8

N -((R )-1-(4-胺基-6-(三氟甲基)吡啶-2-基)乙基)-7-((1R ,4R )-2-氧雜-5-氮雜雙環[2.2.1]庚-5-基)-4-甲基呔

-1-胺 鹽酸鹽 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.26 (s, 1H), 8.13 (d,J = 9.2 Hz, 1H), 7.62 (s, 1H), 7.45 (d,J = 9.1 Hz, 1H), 6.82 (s, 1H), 6.75 (s, 1H), 5.18 - 5.14 (m, 2H), 4.82 (s, 1H), 3.92 (d,J = 7.5 Hz, 1H), 3.75 (d,J = 7.6 Hz, 1H), 3.69 (d,J = 10.6 Hz, 1H), 3.46 - 3.39 (m, 1H), 2.75 (s, 3H), 2.04 (s, 2H), 1.67 (d,J = 7.0 Hz, 3H)。LCMS [M+1]⁺ : 445.2。 16-9

(R )-N -(1-(4-胺基-6-(三氟甲基)吡啶-2-基)乙基)-7-(3-(二甲基胺基)-3-甲基氮雜環丁烷-1-基)-4-甲基呔

-1-胺 鹽酸鹽 ¹ H NMR (400 MHz, CD₃ OD) δ = 8.26 (d,J = 9.1 Hz, 1H), 7.64 (d,J = 2.2 Hz, 1H), 7.33 (dd,J = 9.0, 2.2 Hz, 1H), 7.08 (q,J = 2.3 Hz, 2H), 5.25 (q,J = 7.0 Hz, 1H), 4.60 (dd,J = 14.5, 9.9 Hz, 2H), 4.34 (t,J = 10.2 Hz, 2H), 2.96 (s, 6H), 2.83 (s, 3H), 1.85 (s, 3H), 1.81 (d,J = 7.1 Hz, 3H)。LCMS [M+1]⁺ : 460.2。 16-10

(R )-1-(4-((1-(4-胺基-6-(三氟甲基)吡啶-2-基)乙基)胺基)-1-甲基呔

-6-基)-3-甲基氮雜環丁烷-3-醇 ¹ H NMR (400 MHz, CD₃ OD) δ 7.98 (d,J = 8.9 Hz, 1H), 7.15 - 7.07 (m, 2H), 6.83 - 6.74 (m, 2H), 5.25 (q,J = 6.9 Hz, 1H), 4.60 (s, 1H), 4.11 (dd,J = 8.5, 3.2 Hz, 2H), 4.02 (d,J = 8.5 Hz, 2H), 2.69 (s, 3H), 1.66 (d,J = 7.0 Hz, 3H), 1.63 (s, 3H)。LCMS [M+1]⁺ : 433.2。 16-11

(R )-N -(1-(4-胺基-6-(三氟甲基)吡啶-2-基)乙基)-7-(3-(二甲基胺基)-3-甲基氮雜環丁烷-1-基)-4-甲基吡啶并[3,4-d ]嗒

-1-胺 二鹽酸鹽 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 15.06 (s, 1H), 12.63 (s, 1H), 9.31 (s, 1H), 9.01 (s, 1H), 7.78 (s, 1H), 6.90 (s, 1H), 6.81 (s, 1H), 6.76 (s, 1H), 5.17 - 5.09 (m, 1H), 4.65 (dd,J = 10.2, 6.0 Hz, 2H), 4.25 (s, 2H), 4.17 (d,J = 10.7 Hz, 2H), 2.81 (s, 3H), 2.71 (s, 6H), 1.70 (s, 3H), 1.66 (d,J = 7.0 Hz, 2H)。LCMS [M+1]⁺ : 461.2。 16-12

(R)-N-(1-(4-胺基-6-(三氟甲基)吡啶-2-基)乙基)-4-甲基-7-(4-甲基哌

-1-基)吡啶并[3,4-d]嗒

-1-胺 ¹ H NMR (400 MHz, CD₃ OD) δ = 9.02 (s, 1H), 7.29 (s, 1H), 6.79 - 6.71 (m, 2H), 5.29 (q,J = 6.9 Hz, 1H), 3.87 - 3.80 (m, 4H), 2.64 (s, 3H), 2.63 - 2.58 (m, 4H), 2.38 (s, 3H), 1.62 (d,J = 7.0 Hz, 3H)。LCMS [M+1]⁺ : 447.3。 16-13

N -((R )-1-(4-胺基-6-(三氟甲基)吡啶-2-基)乙基)-7-(6-氧雜-3-氮雜雙環[3.1.1]庚-3-基)-4-甲基吡啶并[3,4-d ]嗒

-1-胺 ¹ H NMR (400 MHz, CD₃ OD) δ = 9.08 (s, 1H), 7.16 (s, 1H), 6.82 - 6.75 (m, 2H), 5.34 (q,J = 7.0 Hz, 1H), 3.98 (d,J = 13.1 Hz, 2H), 3.83 (d,J = 12.6 Hz, 2H), 3.41 - 3.35 (m, 2H), 2.68 (s, 3H), 2.05 (d,J = 9.0 Hz, 1H), 1.66 (d,J = 7.0 Hz, 3H)。LCMS [M+1]⁺ : 446.2。 16-14

N -((R )-1-(3-胺基-4-氟-5-(三氟甲基)苯基)乙基)-7-((1R ,4R )-2-氧雜-5-氮雜雙環[2.2.1]庚-5-基)-4-甲基呔

-1-胺 ¹ H NMR (400 MHz, DMSO-d ₆ )δ = 7.77 (d,J = 9.6 Hz, 1H), 7.26 - 7.24 (m, 2H), 7.08-7.06 (m, 2H), 6.85 (d,J = 6.0 Hz, 1H), 5.52(s, 2H), 5.37 - 5.33 (m, 1H), 4.90 (s, 1H), 4.74 (s, 1H), 3.86 (d,J = 7.6 Hz, 1H), 3.71 - 3.60 (m, 2H), 3.22 (d,J = 9.6 Hz, 1H), 2.53 (s, 3H), 2.02 - 1.93 (m, 2H), 1.54 (d,J = 6.8 Hz, 3H)。LCMS [M+1]⁺ : 462.4。 實例17-1 (R )-2-甲氧基-3-(1-((4-甲基-7-

啉基吡啶并[3,4-d ]嗒

-1-基)胺基)乙基)苯甲腈

Following the teaching of General Reaction Scheme III and the method of preparing Examples 16-1-16-2, the following compounds of formula (I), Examples 16-3-16-14, as shown in Table 16, were prepared. Table 16 Example # structure Spectral data 16-3

( R ) -N -(1-(4-amino-6-(trifluoromethyl)pyridin-2-yl)ethyl)-4-methyl-7-

Hydroxypyrido[3,4- d ]

-1-amine ¹ H NMR (400 MHz, CD ₃ OD) δ 9.03 (s, 1H), 7.27 (s, 1H), 6.79-6.72 (m, 2H), 5.29 (q, J = 6.8 Hz, 1H), 3.86-3.79 (m, 4H), 3.75-3.70 (m, 4H), 1.63 (d, J = 6.8 Hz, 3H). LCMS [M+1] ⁺ : 434.2. 16-4

N -(( R )-1-(4-amino-6-(trifluoromethyl)pyridin-2-yl)ethyl)-7-(6-oxa-3-azabicyclo[3.1.1 ]Hept-3-yl)-4-methyl

-1-amine ¹ H NMR (400 MHz, CD ₃ OD) δ = 7.97 (d, J = 9.2 Hz, 1H), 7.48 (dd, J = 2.4, 9.2 Hz, 1H), 7.30 (d, J = 2.4 Hz, 1H) , 6.78 (q, J =2.0 Hz, 2H), 5.34 (q, J = 6.8 Hz, 1H), 4.90-4.87 (m, 2H), 3.87-3.78 (m, 2H), 3.76-3.68 (m, 2H ), 3.35 (s, 1H), 2.65 (s, 3H), 2.06 (d, J = 9.2 Hz, 1H), 1.64 (d, J = 6.8 Hz, 3H). LCMS [M+1] ⁺ : 445.2. 16-5

N -(( R )-1-(4-amino-6-(trifluoromethyl)pyridin-2-yl)ethyl)-4-methyl-7-((1 R ,4 R )-5 -Methyl-2,5-diazabicyclo[2.2.2]oct-2-yl)

-1-amine hydrochloride ¹ H NMR (400 MHz, CD ₃ OD) δ = 8.30 (d, J = 9.2 Hz, 1H), 7.87 (br s, 1H), 7.66 (br d, J = 9.2 Hz, 1H), 7.25 (br s , 1H), 7.17 (s, 1H), 5.46-5.18 (m, 1H), 4.98-4.94 (m, 1H), 4.45-4.19 (m, 1H), 4.16-3.83 (m, 3H), 3.56-3.36 (m, 1H), 3.11 (s, 3H), 2.85 (s, 3H), 2.62-2.38 (m, 1H), 2.36-2.04 (m, 3H), 1.87 (br d, J = 7.2 Hz, 3H) . LCMS [M+1] ⁺ : 472.2. 16-6

N -(( R )-1-(4-amino-6-(trifluoromethyl)pyridin-2-yl)ethyl)-4-methyl-7-((1 R ,4 R )-5 -Methyl-2,5-diazabicyclo[2.2.2]oct-2-yl)pyrido[3,4- d ]

-1-amine hydrochloride ¹ H NMR (400 MHz, CD ₃ OD δ = 9.37 (s, 1H), 8.18-7.44 (m, 1H), 7.31-7.23 (m, 1H), 7.19 (d, J = 2.0 Hz, 1H), 5.69 -5.39 (m, 1H), 5.29 (br dd, J = 5.2, 6.8 Hz, 1H), 4.36 (br d, J = 13.6 Hz, 1H), 4.06 (br d, J = 11.6 Hz, 3H), 3.53 -3.36 (m, 1H), 3.11 (s, 3H), 2.89 (s, 3H), 2.61-2.38 (m, 1H), 2.06-2.30 (m, 3H), 1.87 (br dd, J = 2.4, 6.8 Hz, 3H). LCMS [M+1] ⁺ : 473.2. 16-7

( R )-2-(1-((1-(4-amino-6-(trifluoromethyl)pyridin-2-yl)ethyl)amino)-4-methylpyrido(3,4 -d ] Da

-7-yl)-6-methyl-2,6-diazaspiro[3.4]oct-5-one hydrochloride ¹ H NMR (400 MHz, CD ₃ OD) δ = 9.22 (s, 1H), 7.34 (s, 1H), 7.09 (d, J = 2.0 Hz, 1H), 7.04 (br s, 1H), 5.20 (q , J = 7.2 Hz, 1H), 4.48 (dd, J = 3.6, 9.6 Hz, 2H), 4.30 (br t, J = 9.6 Hz, 2H), 3.49 (t, J = 6.8 Hz, 2H), 2.93 ( s, 3H), 2.83 (s, 3H), 2.55 (t, J = 6.8 Hz, 2H), 1.78 (d, J = 6.8 Hz, 3H). LCMS [M+1] ⁺ : 487.2. 16-8

N -(( R )-1-(4-amino-6-(trifluoromethyl)pyridin-2-yl)ethyl)-7-((1 R ,4 R )-2-oxa-5 -Azabicyclo[2.2.1]hept-5-yl)-4-methyl

-1-amine hydrochloride ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.26 (s, 1H), 8.13 (d, J = 9.2 Hz, 1H), 7.62 (s, 1H), 7.45 (d, J = 9.1 Hz, 1H) , 6.82 (s, 1H), 6.75 (s, 1H), 5.18-5.14 (m, 2H), 4.82 (s, 1H), 3.92 (d, J = 7.5 Hz, 1H), 3.75 (d, J = 7.6 Hz, 1H), 3.69 (d, J = 10.6 Hz, 1H), 3.46-3.39 (m, 1H), 2.75 (s, 3H), 2.04 (s, 2H), 1.67 (d, J = 7.0 Hz, 3H ). LCMS [M+1] ⁺ : 445.2. 16-9

( R ) -N -(1-(4-amino-6-(trifluoromethyl)pyridin-2-yl)ethyl)-7-(3-(dimethylamino)-3-methyl Azetidine-1-yl)-4-methyl

-1-amine hydrochloride ¹ H NMR (400 MHz, CD ₃ OD) δ = 8.26 (d, J = 9.1 Hz, 1H), 7.64 (d, J = 2.2 Hz, 1H), 7.33 (dd, J = 9.0, 2.2 Hz, 1H) , 7.08 (q, J = 2.3 Hz, 2H), 5.25 (q, J = 7.0 Hz, 1H), 4.60 (dd, J = 14.5, 9.9 Hz, 2H), 4.34 (t, J = 10.2 Hz, 2H) , 2.96 (s, 6H), 2.83 (s, 3H), 1.85 (s, 3H), 1.81 (d, J = 7.1 Hz, 3H). LCMS [M+1] ⁺ : 460.2. 16-10

( R )-1-(4-((1-(4-amino-6-(trifluoromethyl)pyridin-2-yl)ethyl)amino)-1-methyl

-6-yl)-3-methylazetidine-3-ol ¹ H NMR (400 MHz, CD ₃ OD) δ 7.98 (d, J = 8.9 Hz, 1H), 7.15-7.07 (m, 2H), 6.83-6.74 (m, 2H), 5.25 (q, J = 6.9 Hz) , 1H), 4.60 (s, 1H), 4.11 (dd, J = 8.5, 3.2 Hz, 2H), 4.02 (d, J = 8.5 Hz, 2H), 2.69 (s, 3H), 1.66 (d, J = 7.0 Hz, 3H), 1.63 (s, 3H). LCMS [M+1] ⁺ : 433.2. 16-11

( R ) -N -(1-(4-amino-6-(trifluoromethyl)pyridin-2-yl)ethyl)-7-(3-(dimethylamino)-3-methyl Azetidine-1-yl)-4-methylpyrido[3,4- d ]

-1-amine dihydrochloride ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 15.06 (s, 1H), 12.63 (s, 1H), 9.31 (s, 1H), 9.01 (s, 1H), 7.78 (s, 1H), 6.90 (s, 1H), 6.81 (s, 1H), 6.76 (s, 1H), 5.17-5.09 (m, 1H), 4.65 (dd, J = 10.2, 6.0 Hz, 2H), 4.25 (s, 2H), 4.17 (d, J = 10.7 Hz, 2H), 2.81 (s, 3H), 2.71 (s, 6H), 1.70 (s, 3H), 1.66 (d, J = 7.0 Hz, 2H). LCMS [M+1] ⁺ : 461.2. 16-12

(R)-N-(1-(4-Amino-6-(trifluoromethyl)pyridin-2-yl)ethyl)-4-methyl-7-(4-methylpiper

-1-yl)pyrido[3,4-d]ta

-1-amine ¹ H NMR (400 MHz, CD ₃ OD) δ = 9.02 (s, 1H), 7.29 (s, 1H), 6.79-6.71 (m, 2H), 5.29 (q, J = 6.9 Hz, 1H), 3.87- 3.80 (m, 4H), 2.64 (s, 3H), 2.63-2.58 (m, 4H), 2.38 (s, 3H), 1.62 (d, J = 7.0 Hz, 3H). LCMS [M+1] ⁺ : 447.3. 16-13

N -(( R )-1-(4-amino-6-(trifluoromethyl)pyridin-2-yl)ethyl)-7-(6-oxa-3-azabicyclo[3.1.1 ]Hept-3-yl)-4-methylpyrido[3,4- d ]a

-1-amine ¹ H NMR (400 MHz, CD ₃ OD) δ = 9.08 (s, 1H), 7.16 (s, 1H), 6.82-6.75 (m, 2H), 5.34 (q, J = 7.0 Hz, 1H), 3.98 ( d, J = 13.1 Hz, 2H), 3.83 (d, J = 12.6 Hz, 2H), 3.41-3.35 (m, 2H), 2.68 (s, 3H), 2.05 (d, J = 9.0 Hz, 1H), 1.66 (d, J = 7.0 Hz, 3H). LCMS [M+1] ⁺ : 446.2. 16-14

N -(( R )-1-(3-amino-4-fluoro-5-(trifluoromethyl)phenyl)ethyl)-7-((1 R ,4 R )-2-oxa- 5-azabicyclo[2.2.1]hept-5-yl)-4-methyl

-1-amine ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 7.77 (d, J = 9.6 Hz, 1H), 7.26-7.24 (m, 2H), 7.08-7.06 (m, 2H), 6.85 (d, J = 6.0 Hz, 1H), 5.52(s, 2H), 5.37-5.33 (m, 1H), 4.90 (s, 1H), 4.74 (s, 1H), 3.86 (d, J = 7.6 Hz, 1H), 3.71- 3.60 (m, 2H), 3.22 (d, J = 9.6 Hz, 1H), 2.53 (s, 3H), 2.02-1.93 (m, 2H), 1.54 (d, J = 6.8 Hz, 3H). LCMS [M+1] ⁺ : 462.4. Example 17-1 ( R )-2-methoxy-3-(1-((4-methyl-7-

Hydroxypyrido[3,4- d ]

-1-yl)amino)ethyl)benzonitrile

Step A: To 1-(3-bromo-2-methoxyphenyl)ethan-1-one (1.00 g, 4.37 mmol, 1.00 equivalent) and ( S )-2-methylpropane-2-sulfinyl Amine (688 mg, 5.68 mmol, 1.30 equivalents) in THF (15.0 mL) was added titanium (IV) butoxide (1.99 g, 8.73 mmol, 1.81 mL, 2.00 equivalents) and 1,2-dimethoxy Ethane (393 mg, 4.37 mmol, 454 µL, 1.00 equivalent), and the mixture was stirred at 70°C for 12 hours. The mixture was then diluted with ethyl acetate (50.0 mL) and water (5.00 mL), and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 20/1 to 10/1) to obtain ( S , E ) - N - (1- (3- bromo-2-methoxyphenyl) extending ethyl) -2-methyl-sulfinyl-2-amine (1.25 g, 3.76 mmol, 86.2 % yield).

Step B: To ( S , E ) -N -(1-(3-bromo-2-methoxyphenyl)ethylene)-2-methylpropane-2-sulfinic acid at -60°C To a solution of amine (1.25 g, 3.76 mmol, 1.00 equivalent) in THF (15.0 mL) was added lithium tri-secondbutylborohydride (1.0 M in THF, 5.64 mL, 1.50 equivalent) dropwise. After the addition was complete, the mixture was warmed to 30°C and stirred for 30 minutes, then diluted with water (5.00 mL) and extracted with ethyl acetate (30.0 mL×2). The combined organic phase was concentrated under reduced pressure, and the residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 5/1 to 3/1) to obtain ( S )- N -(( R )-1-(3-bromo-2-methoxyphenyl)ethyl)-2-methylpropane-2-sulfinamide (900 mg, 2.69 mmol, 71.6% Yield).

¹ H NMR (400 MHz, CDCl ₃ ) δ = 7.52-7.44 (m, 1H), 7.34-7.29 (m, 1H), 7.01 (t, J = 7.6 Hz, 1H), 5.05-4.95 (m, 1H) , 3.92 (s, 3H), 1.50 (d, J = 6.8 Hz, 3H), 1.21 (s, 9H).

Step C: To ( S ) -N -(( R )-1-(3-bromo-2-methoxyphenyl)ethyl)-2-methylpropane-2-sulfinamide (900 mg, 2.69 mmol, 1.00 equivalent) was _{added to a solution of THF (12.0 mL) and H 2} O (3.00 mL) with iodine (205 mg, 808 µmol, 163 µL, 0.30 equivalent), and the mixture was stirred at 50°C for 1 hour . The mixture was then diluted with ethyl acetate (30.0 mL), washed with aqueous sodium sulfite (20.0 mL), and further washed with brine (20.0 mL). The organic phase was dried and concentrated under reduced pressure, and then _{purified by column chromatography (SiO 2} , dichloromethane/methanol = 1/0 to 40/1) to obtain ( R )-1 as a yellow oil -(3-Bromo-2-methoxyphenyl)ethan-1-amine (500 mg, 2.17 mmol, 80.7% yield).

（300 mg，1.40 mmol，1.00當量）於DMSO（5.00 mL）中之溶液中添加氟化銫（319 mg，2.10 mmol，77.5 µL，1.50當量）及(R )-1-(3-溴-2-甲氧基苯基)乙-1-胺（322 mg，1.40 mmol，1.00當量），且將混合物在130℃下攪拌30分鐘。隨後將混合物用乙酸乙酯（50.0 mL）稀釋，且用鹽水（30.0 mL×3）洗滌。將分離的有機相乾燥且在減壓下濃縮，且將殘餘物藉由管柱層析法（SiO₂ ，石油醚/乙酸乙酯＝5/1至4/1）純化，得到呈黃色固體狀之(R )-N -(1-(3-溴-2-甲氧基苯基)乙基)-7-氯-4-甲基吡啶并[3,4-d ]嗒

-1-胺（250 mg，613 µmol，43.8%產率）。Step D: To 1,7-dichloro-4-methylpyrido[3,4- d ]

(300 mg, 1.40 mmol, 1.00 equivalent) in DMSO (5.00 mL) was added cesium fluoride (319 mg, 2.10 mmol, 77.5 µL, 1.50 equivalent) and ( R )-1-(3-bromo-2) -Methoxyphenyl)ethan-1-amine (322 mg, 1.40 mmol, 1.00 equivalent), and the mixture was stirred at 130°C for 30 minutes. The mixture was then diluted with ethyl acetate (50.0 mL), and washed with brine (30.0 mL×3). The separated organic phase was dried and concentrated under reduced pressure, and the residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 5/1 to 4/1) to obtain a yellow solid The ( R ) -N -(1-(3-bromo-2-methoxyphenyl)ethyl)-7-chloro-4-methylpyrido[3,4- d ]

-1-amine (250 mg, 613 µmol, 43.8% yield).

-1-胺（200 mg，491 µmol，1.00當量）於DMSO（0.80 mL）中之溶液中添加氟化銫（112 mg，736 µmol，27.1 µL，1.50當量）及

啉（192 mg，2.21 mmol，194 µL，4.50當量）。將混合物在130℃下攪拌30分鐘，隨後用水（20.0 mL）稀釋且過濾。將沈澱物真空乾燥，得到呈黃色固體狀之(R )-N -(1-(3-溴-2-甲氧基苯基)乙基)-4-甲基-7-

啉基吡啶并[3,4-d ]嗒

-1-胺（200 mg，436 µmol，產率89.0%）。LCMS [M+1]⁺ : 460.1。Step E: To ( R ) -N -(1-(3-bromo-2-methoxyphenyl)ethyl)-7-chloro-4-methylpyrido[3,4- d ]

A solution of -1-amine (200 mg, 491 µmol, 1.00 equivalent) in DMSO (0.80 mL) was added with cesium fluoride (112 mg, 736 µmol, 27.1 µL, 1.50 equivalent) and

Morpholine (192 mg, 2.21 mmol, 194 µL, 4.50 equivalents). The mixture was stirred at 130°C for 30 minutes, then diluted with water (20.0 mL) and filtered. The precipitate was dried in vacuo to obtain ( R ) -N -(1-(3-bromo-2-methoxyphenyl)ethyl)-4-methyl-7- as a yellow solid

Hydroxypyrido[3,4- d ]

-1-amine (200 mg, 436 µmol, yield 89.0%). LCMS [M+1] ⁺ : 460.1.

啉基吡啶并[3,4-d ]嗒

-1-胺（180 mg，393 µmol，1.00當量）、氰化鋅（92.2 mg，785 µmol，49.9 µL，2.00當量）、DPPF（43.5 mg，78.5 µmol，0.20當量）、鋅粉塵（2.57 mg，39.3 µmol，0.10當量）及Pd₂ (dba)₃ （36.0 mg，39.3 µmol，0.10當量）於N,N- 二甲基乙醯胺（4.00 mL）中之混合物脫氣且用氮氣沖洗（3次），且將該混合物在氮氣氛圍下在120℃下攪拌6小時。將反應混合物用乙酸乙酯（100 mL）稀釋且過濾。將濾液用鹽水（50.0 mL×3）洗滌，乾燥，且在減壓下濃縮。將殘餘物藉由製備型HPLC[管柱：Phenomenex luna C18 150×25 mm×10 um；移動相：A相：水（0.225%甲酸），B相：乙腈；B%：11%-41%]純化，得到呈黃色固體狀之(R )-2-甲氧基-3-(1-((4-甲基-7-

啉基吡啶并[3,4-d ]嗒

-1-基)胺基)乙基)苯甲腈（93.0 mg，226 µmol，57.5%產率，98.2%純度）。LCMS [M+1]⁺ : 405.2。Step F: Add ( R ) -N -(1-(3-bromo-2-methoxyphenyl)ethyl)-4-methyl-7-

Hydroxypyrido[3,4- d ]

-1-amine (180 mg, 393 µmol, 1.00 equivalent), zinc cyanide (92.2 mg, 785 µmol, 49.9 µL, 2.00 equivalent), DPPF (43.5 mg, 78.5 µmol, 0.20 equivalent), zinc dust (2.57 mg, The mixture of 39.3 µmol, 0.10 equivalent) and Pd ₂ (dba) ₃ (36.0 mg, 39.3 µmol, 0.10 equivalent) in N,N -dimethylacetamide (4.00 mL) was degassed and flushed with nitrogen (3 times) ), and the mixture was stirred at 120°C for 6 hours under a nitrogen atmosphere. The reaction mixture was diluted with ethyl acetate (100 mL) and filtered. The filtrate was washed with brine (50.0 mL×3), dried, and concentrated under reduced pressure. The residue was subjected to preparative HPLC [column: Phenomenex luna C18 150×25 mm×10 um; mobile phase: phase A: water (0.225% formic acid), phase B: acetonitrile; B%: 11%-41%] Purified to obtain ( R )-2-methoxy-3-(1-((4-methyl-7-

Hydroxypyrido[3,4- d ]

-1-yl)amino)ethyl)benzonitrile (93.0 mg, 226 µmol, 57.5% yield, 98.2% purity). LCMS [M+1] ⁺ : 405.2.

并[2,1-c ][1,4]

-8(1H )-基)-4-甲基吡啶并[3,4-d ]嗒

-1-基)胺基)乙基)-2-甲氧基苯甲腈

¹ H NMR (400 MHz, CD ₃ OD) δ = 9.11 (s, 1H), 8.49 (s, 1H), 7.70-7.64 (m, 1H), 7.54-7.49 (m, 1H), 7.43 (s, 1H) ), 7.15 (t, J = 7.6 Hz, 1H), 5.66-5.55 (m, 1H), 4.20 (s, 3H), 3.85 (s, 8H), 2.69 (s, 3H), 1.62 (d, J = 6.8 Hz, 3H). Example 17-2 3-(( R )-1-((7-(( S )-hexahydropyridine

And [2,1- c ][1,4]

-8(1 H )-yl)-4-methylpyrido[3,4- d ]

-1-yl)amino)ethyl)-2-methoxybenzonitrile

Step A: Add Boc to a solution of (R )-1-(3-bromo-2-methoxyphenyl)ethan-1-amine (1.20 g, 5.22 mmol, 1.00 equivalent) in THF (20.0 mL) ₂ O (1.48 g, 6.78 mmol, 1.56 mL, 1.30 equivalents), and the mixture was stirred at 25°C for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 200/1 to 30/1) to obtain ( R )-(1-(3-bromo- Tertiary butyl 2-methoxyphenyl)ethyl)carbamate (1.50 g, 4.54 mmol, 87.1% yield).

¹ H NMR (400 MHz, CDCl ₃ ) δ = 7.45 (dd, J = 1.6, 8.0 Hz, 1H), 7.22 (d, J = 6.8 Hz, 1H), 6.98 (t, J = 7.6 Hz, 1H), 5.10-4.90 (m, 2H), 3.95 (s, 3H), 1.46-1.35 (m, 12H).

Step B: Combine ( R )-(1-(3-bromo-2-methoxyphenyl)ethyl) carbamic acid tert-butyl ester (1.30 g, 3.94 mmol, 1.00 equivalent), zinc cyanide (925 mg , 7.87 mmol, 500 µL, 2.00 equivalent), zinc dust (25.7 mg, 394 µmol, 0.10 equivalent), DPPF (437 mg, 787 µmol, 0.20 equivalent) and Pd ₂ (dba) ₃ (361 mg, 394 µmol, 0.10 Equivalent) The mixture in N,N -dimethylacetamide (15.0 mL) was degassed and flushed with nitrogen (3 times), and the mixture was stirred at 130°C for 5 hours under a nitrogen atmosphere. The mixture was then diluted with ethyl acetate (100 mL), filtered, and the filtrate was washed with brine (50.0 mL×3), dried and concentrated under reduced pressure. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 50/1 to 20/1) to obtain ( R )-(1-(3-cyano- Tertiary butyl 2-methoxyphenyl)ethyl)carbamate (0.90 g, 3.26 mmol, 82.7% yield).

¹ H NMR (400 MHz, CDCl ₃ ) δ = 7.50 (d, J = 8.0 Hz, 2H), 7.14 (t, J = 7.6 Hz, 1H), 5.09-4.91 (m, 2H), 4.15 (s, 3H) ), 1.54-1.32 (m, 12H).

Step C: To tert-butyl (R )-(1-(3-cyano-2-methoxyphenyl)ethyl)carbamate (0.90 g, 3.26 mmol, 1.00 equivalent) in DCM (2.00 mL) TFA (6.93 g, 60.8 mmol, 4.50 mL, 18.7 equivalents) was added to the solution in Zhong, and the mixture was stirred at 20°C for 30 minutes. The mixture was then concentrated under reduced pressure, and the pH was adjusted to pH=7 with saturated aqueous sodium bicarbonate solution. The resulting mixture was extracted with a dichloromethane/methanol 10:1 solution (50.0 mL), and the organic phase was dried and concentrated to obtain ( R )-3-(1-aminoethyl)-2 as a brown oil -Methoxybenzonitrile (600 mg, crude).

¹ H NMR (400 MHz, CDCl ₃ ) δ = 7.66 (dd, J = 1.2, 7.6 Hz, 1H), 7.53 (dd, J = 1.2, 7.6 Hz, 1H), 7.17 (t, J = 8.0 Hz, 1H ), 4.52 (q, J = 6.8 Hz, 1H), 4.13 (s, 3H), 1.46 (d, J = 6.4 Hz, 3H).

（300 mg，1.40 mmol，1.00當量）於DMSO（5.00 mL）中之溶液中添加氟化銫（319 mg，2.10 mmol，77.5 µL，1.50當量）及(R )-3-(1-胺基乙基)-2-甲氧基苯甲腈（247 mg，1.40 mmol，1.00當量），且將混合物在130℃下攪拌30分鐘。將反應混合物用乙酸乙酯（50.0 mL）稀釋，用鹽水（20.0 mL×3）洗滌，且將分離的有機相乾燥，且在減壓下濃縮。將殘餘物藉由製備型HPLC[管柱：Phenomenex luna C18 150×40 mm×15 um；移動相：A相：水（0.1% TFA），B相：乙腈；B%：14%-44%]純化，得到呈黃色固體狀之(R )-3-(1-((7-氯-4-甲基吡啶并[3,4-d ]嗒

-1-基)胺基)乙基)-2-甲氧基苯甲腈（200 mg，565 µmol，40.3%產率）。LCMS [M+1]⁺ : 354.1。Step D: In 1,7-dichloro-4-methylpyrido[3,4-d]

(300 mg, 1.40 mmol, 1.00 equivalent) in DMSO (5.00 mL) was added cesium fluoride (319 mg, 2.10 mmol, 77.5 µL, 1.50 equivalent) and ( R )-3-(1-aminoethyl) Yl)-2-methoxybenzonitrile (247 mg, 1.40 mmol, 1.00 equivalent), and the mixture was stirred at 130°C for 30 minutes. The reaction mixture was diluted with ethyl acetate (50.0 mL), washed with brine (20.0 mL×3), and the separated organic phase was dried and concentrated under reduced pressure. The residue was subjected to preparative HPLC [column: Phenomenex luna C18 150×40 mm×15 um; mobile phase: phase A: water (0.1% TFA), phase B: acetonitrile; B%: 14%-44%] Purified to obtain ( R )-3-(1-((7-chloro-4-methylpyrido[3,4- d ]

-1-yl)amino)ethyl)-2-methoxybenzonitrile (200 mg, 565 µmol, 40.3% yield). LCMS [M+1] ⁺ : 354.1.

-1-基)胺基)乙基)-2-甲氧基苯甲腈（30.0 mg，84.8 µmol，1.00當量）、(S )-八氫吡

并[2,1-c ][1,4]

（27.4 mg，127 µmol，1.50當量，二鹽酸鹽）、N,N- 二異丙基乙胺（32.9 mg，254 µmol，44.3 µL，3.00當量）及氟化銫（19.3 mg，127 µmol，4.69 µL，1.50當量於DMSO（0.40 mL）中之混合物在氮氣氛圍下在130℃下攪拌2小時。隨後將混合物用乙酸乙酯（30.0 mL）稀釋，用鹽水（10.0 mL×3）洗滌，且將分離的有機相乾燥且在減壓下濃縮。將殘餘物藉由製備型HPLC[管柱：3_Phenomenex Luna C18 75×30 mm×3 um；移動相：A相：水（0.05% HCl），B相：乙腈；B%：10%-30%]純化，得到呈黃色固體狀之3-((R )-1-((7-((S )-六氫吡

并[2,1-c ][1,4]

-8(1H )-基)-4-甲基吡啶并[3,4-d ]嗒

-1-基)胺基)乙基)-2-甲氧基苯甲腈（13.9 mg，27.8 µmol，32.8%產率，99.3%純度，HCl鹽）。LCMS [M+1]⁺ : 460.2。Step E: Add ( R )-3-(1-((7-chloro-4-methylpyrido[3,4- d ]

-1-yl)amino)ethyl)-2-methoxybenzonitrile (30.0 mg, 84.8 µmol, 1.00 equivalent), ( S )-octahydropyridine

And [2,1- c ][1,4]

(27.4 mg, 127 µmol, 1.50 equivalent, dihydrochloride), N,N -diisopropylethylamine (32.9 mg, 254 µmol, 44.3 µL, 3.00 equivalent) and cesium fluoride (19.3 mg, 127 µmol, A mixture of 4.69 µL, 1.50 equivalents in DMSO (0.40 mL) was stirred under a nitrogen atmosphere at 130°C for 2 hours. The mixture was then diluted with ethyl acetate (30.0 mL), washed with brine (10.0 mL×3), and The separated organic phase was dried and concentrated under reduced pressure. The residue was subjected to preparative HPLC [column: 3_Phenomenex Luna C18 75×30 mm×3 um; mobile phase: phase A: water (0.05% HCl), B Phase: Acetonitrile; B%: 10%-30%] purified to obtain 3-(( R )-1-((7-(( S )-hexahydropyridine) as a yellow solid

And [2,1- c ][1,4]

-8(1 H )-yl)-4-methylpyrido[3,4- d ]

-1-yl)amino)ethyl)-2-methoxybenzonitrile (13.9 mg, 27.8 µmol, 32.8% yield, 99.3% purity, HCl salt). LCMS [M+1] ⁺ : 460.2.

¹ H NMR (400 MHz, CD ₃ OD) δ = 9.35 (s, 1H), 7.91 (s, 1H), 7.79 (br d, J = 7.6 Hz, 1H), 7.65-7.53 (m, 1H), 7.21 (t, J = 8.0 Hz, 1H), 5.66-5.54 (m, 1H), 5.25-5.05 (m, 2H), 4.29-4.14 (m, 5H), 4.08-3.97 (m, 1H), 3.86-3.62 (m, 4H), 3.58 (br d, J = 11.2 Hz, 1H), 3.52-3.35 (m, 3H), 2.86 (s, 3H), 1.71 (d, J = 6.8 Hz, 3H).

(R )-3-(1-((7-(3-羥基-3-甲基氮雜環丁烷-1-基)-4-甲基吡啶并[3,4-d ]嗒

-1-基)胺基)乙基)-2-甲氧基苯甲腈 ¹ H NMR (400 MHz, CD₃ OD) δ = 8.96 (s, 1H), 7.67 (dd,J = 1.6, 8.0 Hz, 1H), 7.52 (dd,J = 1.6, 7.6 Hz, 1H), 7.15 (t,J = 8.0 Hz, 1H), 7.07 (s, 1H), 5.69 (q,J = 6.8 Hz, 1H), 4.24 (s, 3H), 4.17 - 4.05 (m, 4H), 2.63 (s, 3H), 1.66 - 1.59 (m, 6H)。LCMS [M+1]⁺ : 405.2。 17-4

(R )-3-(1-((7-(3-羥基-3-甲基氮雜環丁烷-1-基)-4-甲基呔

-1-基)胺基)乙基)-2-甲氧基苯甲腈 ¹ H NMR (400 MHz, CD₃ OD) δ = 7.86 (br d,J = 9.2 Hz, 1H), 7.67 (dd,J = 1.6, 7.6 Hz, 1H), 7.48 (dd,J = 1.6, 7.6 Hz, 1H), 7.16 (s, 1H), 7.11 (t,J = 8.0 Hz, 1H), 7.08 - 7.03 (m, 1H), 5.70 (q,J = 6.8 Hz, 1H), 4.23 (s, 3H), 4.05 (br d,J = 8.0 Hz, 2H), 3.95 (br d,J = 8.4 Hz, 2H), 2.59 (s, 3H), 1.63 - 1.59 (m, 6H)。LCMS [M+1]⁺ : 404.3。 實例18-1 (R )-6-氟-4-甲基-N -(1-(2-甲基-3-(三氟甲基)苯基)乙基)-7-(哌

-1-基)呔

-1-胺

Following the teaching of General Reaction Scheme III and the method of preparing Examples 17-1-17-2, the following compounds of formula (I), Example 17-3-17-4, as shown in Table 17, were prepared. Table 17 Example # structure Spectral data 17-3

( R )-3-(1-((7-(3-hydroxy-3-methylazetidin-1-yl)-4-methylpyrido[3,4- d ]

-1-yl)amino)ethyl)-2-methoxybenzonitrile ¹ H NMR (400 MHz, CD ₃ OD) δ = 8.96 (s, 1H), 7.67 (dd, J = 1.6, 8.0 Hz, 1H), 7.52 (dd, J = 1.6, 7.6 Hz, 1H), 7.15 ( t, J = 8.0 Hz, 1H), 7.07 (s, 1H), 5.69 (q, J = 6.8 Hz, 1H), 4.24 (s, 3H), 4.17-4.05 (m, 4H), 2.63 (s, 3H ), 1.66-1.59 (m, 6H). LCMS [M+1] ⁺ : 405.2. 17-4

( R )-3-(1-((7-(3-hydroxy-3-methylazetidin-1-yl)-4-methyl

-1-yl)amino)ethyl)-2-methoxybenzonitrile ¹ H NMR (400 MHz, CD ₃ OD) δ = 7.86 (br d, J = 9.2 Hz, 1H), 7.67 (dd, J = 1.6, 7.6 Hz, 1H), 7.48 (dd, J = 1.6, 7.6 Hz , 1H), 7.16 (s, 1H), 7.11 (t, J = 8.0 Hz, 1H), 7.08-7.03 (m, 1H), 5.70 (q, J = 6.8 Hz, 1H), 4.23 (s, 3H) , 4.05 (br d, J = 8.0 Hz, 2H), 3.95 (br d, J = 8.4 Hz, 2H), 2.59 (s, 3H), 1.63-1.59 (m, 6H). LCMS [M+1] ⁺ : 404.3. Example 18-1 ( R )-6-fluoro-4-methyl- N -(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-7-(piper

-1-base) 呔

-1-amine

烷（20.0 mL）中之溶液中添加Pd(PPh₃ )₂ Cl₂ （60.0 mg，0.08 mmol，0.02當量）。將反應混合物在氮氣氛圍下在80℃下攪拌12小時。將反應混合物冷卻至25℃，藉由添加飽和氟化鉀水溶液（100 mL）來淬滅，且用乙酸乙酯（200 mL×3）萃取。將合併之有機層用鹽水（200 mL×3）洗滌，經硫酸鈉乾燥，過濾，且在減壓下濃縮，得到呈褐色油狀之化合物5-溴-2-(1-乙氧基乙烯基)-4-氟苯甲酸甲酯（2.00 g，粗製），其直接用於下一步。Step A: Add 5-bromo-4-fluoro-2-iodobenzoic acid methyl ester (1.50 g, 4.18 mmol, 1.00 equivalent) and tributyl(1-ethoxyvinyl)tin (1.52 g, 4.22 mmol, 1.42 mL, 1.01 equivalent) in two

_{Add Pd(PPh 3} ) ₂ Cl ₂ (60.0 mg, 0.08 mmol, 0.02 equivalent) to the solution in alkane (20.0 mL). The reaction mixture was stirred at 80°C for 12 hours under a nitrogen atmosphere. The reaction mixture was cooled to 25°C, quenched by adding saturated aqueous potassium fluoride (100 mL), and extracted with ethyl acetate (200 mL×3). The combined organic layer was washed with brine (200 mL×3), dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the compound 5-bromo-2-(1-ethoxyvinyl) as a brown oil ) Methyl-4-fluorobenzoate (2.00 g, crude), which was used directly in the next step.

To a solution of methyl 5-bromo-2-(1-ethoxyvinyl)-4-fluorobenzoate (2.00 g, crude) in THF (50.0 mL) was added aqueous hydrochloric acid (4.00 M, 10.0 mL, 6.06 equivalent). The mixture was stirred at 25°C for 2 hours, then diluted with water (50.0 mL), and extracted with ethyl acetate (50.0 mL×3). The combined organic layer was washed with brine (20.0 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (petroleum ether/ethyl acetate = 10/1 to 1/1) to obtain the compound 2-acetyl-5-bromo-4-fluorobenzoic acid as a yellow oil Methyl ester (700 mg, 2.54 mmol, 38.6% yield).

¹ H NMR (400 MHz, CDCl ₃ ) δ = 8.14 (d, J = 6.4 Hz, 1H), 7.12 (d, J = 8.0 Hz, 1H), 3.91 (s, 3H), 2.52 (s, 3H).

-1-醇（460 mg，1.79 mmol，70.3%產率）。Step B: Add hydrazine hydrate (130 mg, 2.54 mmol, 98% purity, 1.00 equivalent). The reaction mixture was stirred at 95°C for 30 minutes, then cooled to 25°C and concentrated under reduced pressure to obtain 7-bromo-6-fluoro-4-methylbenzene as a white solid

-1-ol (460 mg, 1.79 mmol, 70.3% yield).

¹ H NMR (400 MHz, CDCl ₃ ) δ = 12.62 (s, 1H), 8.46 (d, J = 7.2 Hz, 1H), 7.94 (d, J = 9.6 Hz, 1H), 2.48 (s, 3H).

-1-醇（250 mg，0.97 mmol，1.00當量）於三氯氧磷（9.52 g，62.1 mmol，5.77 mL，63.8當量）中之混合物在110℃下攪拌2小時。將反應混合物冷卻至25℃，且在減壓下濃縮，得到殘餘物。將殘餘物用乙酸乙酯（30.0 mL）稀釋，且藉由緩慢添加飽和碳酸氫鈉（水溶液）將pH調節至pH＝7。將有機相用鹽水（20.0 mL×2）洗滌，經無水硫酸鈉乾燥，過濾，且在減壓下濃縮。將粗產物藉由製備型TLC（石油醚/乙酸乙酯＝3/1）純化，得到呈黃色固體狀之6-溴-4-氯-7-氟-1-甲基呔

（170 mg，617 µmol，63.5%產率）。LCMS [M+3]⁺ : 276.7。Step C: Add 7-bromo-6-fluoro-4-methyl

A mixture of -1-ol (250 mg, 0.97 mmol, 1.00 equivalent) in phosphorus oxychloride (9.52 g, 62.1 mmol, 5.77 mL, 63.8 equivalent) was stirred at 110°C for 2 hours. The reaction mixture was cooled to 25°C and concentrated under reduced pressure to obtain a residue. The residue was diluted with ethyl acetate (30.0 mL), and the pH was adjusted to pH=7 by slowly adding saturated sodium bicarbonate (aqueous solution). The organic phase was washed with brine (20.0 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative TLC (petroleum ether/ethyl acetate = 3/1) to obtain 6-bromo-4-chloro-7-fluoro-1-methyl as a yellow solid

(170 mg, 617 µmol, 63.5% yield). LCMS [M+3] ⁺ : 276.7.

（170 mg，0.62 mmol，1.00當量）及(R )-1-(2-甲基-3-(三氟甲基)苯基)乙-1-胺（126 mg，0.62 mmol，1.00當量）於DMSO（5.00 mL）中之溶液中添加氟化鉀（180 mg，3.09 mmol，5.00當量）。將混合物在130℃下攪拌12小時，隨後冷卻至25℃，藉由添加水（10.0 mL）來淬滅， 且用乙酸乙酯（20.0 mL×3）萃取。將合併之有機層用鹽水（20.0 mL×3）洗滌，經硫酸鈉乾燥，過濾，且在減壓下濃縮，得到殘餘物。將殘餘物藉由製備型TLC（二氯甲烷/甲醇＝20/1）純化，得到呈黃色油狀之化合物(R )-7-溴-6-氟-4-甲基-N -(1-(2-甲基-3-(三氟甲基)苯基)乙基)呔

-1-胺（80.0 mg，0.18 mmol，29.3%產率）。LCMS [M+3]⁺ : 444.0。Step D: Add 6-bromo-4-chloro-7-fluoro-1-methyl

(170 mg, 0.62 mmol, 1.00 equivalent) and ( R )-1-(2-methyl-3-(trifluoromethyl)phenyl)ethan-1-amine (126 mg, 0.62 mmol, 1.00 equivalent) in Add potassium fluoride (180 mg, 3.09 mmol, 5.00 equivalents) to the solution in DMSO (5.00 mL). The mixture was stirred at 130°C for 12 hours, then cooled to 25°C, quenched by adding water (10.0 mL) , and extracted with ethyl acetate (20.0 mL×3). The combined organic layer was washed with brine (20.0 mL×3), dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by preparative TLC (dichloromethane/methanol=20/1) to obtain compound ( R )-7-bromo-6-fluoro-4-methyl- N -(1- (2-Methyl-3-(trifluoromethyl)phenyl)ethyl)

-1-amine (80.0 mg, 0.18 mmol, 29.3% yield). LCMS [M+3] ⁺ : 444.0.

-1-胺（80.0 mg，0.18 mmol，1.00當量）及哌

（32.0 mg，0.36 mmol，2.00當量）於二

烷（3.00 mL）中之溶液中添加Pd₂ (dba)₃ （16.0 mg，0.02 mmol，0.10當量）、RuPhos（16.0 mg，0.04 mmol，0.20當量）及碳酸銫（300 mg，0.90 mmol，5.00當量）。將反應混合物在氮氣氛圍下在100℃下攪拌12小時，隨後冷卻至25℃，藉由添加水（10.0 mL）來淬滅， 且用乙酸乙酯（20.0 mL×3）萃取。將合併之有機層用鹽水（20.0 mL×3）洗滌，經硫酸鈉乾燥，過濾，且在減壓下濃縮。將殘餘物藉由製備型TLC（二氯甲烷/甲醇=10/1）純化，隨後藉由製備型HPLC[管柱：Phenomenex luna C18 150×25 mm×10 um；移動相：A相：水（0.225%甲酸），B相：乙腈；B%：3%-33%]純化，得到呈黃色固體狀之(R )-6-氟-4-甲基-N -(1-(2-甲基-3-(三氟甲基)苯基)乙基)-7-(哌

-1-基)呔

-1-胺（8.97 mg，0.02 mmol，9.15%產率，91.1%純度，甲酸鹽）。LCMS [M+1]⁺ : 448.2。Step E: Under nitrogen atmosphere, to ( R )-7-bromo-6-fluoro-4-methyl- N -(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl ) Eh

-1-amine (80.0 mg, 0.18 mmol, 1.00 equivalent) and piper

(32.0 mg, 0.36 mmol, 2.00 equivalent) in two

_{Add Pd 2} (dba) ₃ (16.0 mg, 0.02 mmol, 0.10 equivalent), RuPhos (16.0 mg, 0.04 mmol, 0.20 equivalent) and cesium carbonate (300 mg, 0.90 mmol, 5.00 equivalent) to the solution in alkane (3.00 mL) ). The reaction mixture was stirred at 100°C under a nitrogen atmosphere for 12 hours, then cooled to 25°C, quenched by adding water (10.0 mL) , and extracted with ethyl acetate (20.0 mL×3). The combined organic layer was washed with brine (20.0 mL×3), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (dichloromethane/methanol=10/1), followed by preparative HPLC [column: Phenomenex luna C18 150×25 mm×10 um; mobile phase: phase A: water ( 0.225% formic acid), phase B: acetonitrile; B%: 3%-33%] to obtain ( R )-6-fluoro-4-methyl- N -(1-(2-methyl) as a yellow solid -3-(Trifluoromethyl)phenyl)ethyl)-7-(piper

-1-base) 呔

-1-amine (8.97 mg, 0.02 mmol, 9.15% yield, 91.1% purity, formate). LCMS [M+1] ⁺ : 448.2.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 8.30 (s, 1H), 7.86 (d, J = 8.4 Hz, 1H), 7.76 (d, J = 7.6 Hz, 1H), 7.68 (d, J = 14.0 Hz, 1H), 7.61 (d, J = 6.8 Hz, 1H), 7.52 (d, J = 7.6 Hz, 1H), 7.30 (t, J = 7.6 Hz, 1H), 5.70-5.65 (m, 1H ), 3.21 (s, 4H), 3.00 (s, 4H), 2.57 (s, 3H), 2.52 (s, 3H), 1.55 (d, J = 7.2 Hz, 3H).

啉基呔

-1-胺

SFC conditions: column: Chiralcel OD-3 50×4.6mm inner diameter, 3 um; mobile phase: phase A: CO ₂ , phase B: MeOH (0.05% diethylamine); gradient dissolution: MeOH (0.05% diethyl) Amine) in 5% to 40% CO ₂ ; flow rate: 3 ml/min; detector: PDA; column temperature: 35°C; back pressure: 100 Bar. Example 18-2 ( R )-6-fluoro-4-methyl- N -(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-7-

Linyl

-1-amine

-1-胺（60.0 mg，136 µmol，1.00當量）於二

烷（3.00 mL）中之溶液中添加

啉（23.6 mg，271 µmol，23.9 µL，2.00當量）、RuPhos（12.7 mg，27.1 µmol，0.20當量）、Pd₂ (dba)₃ （12.4 mg，13.6 µmol，0.10當量）及碳酸銫（88.4 mg，271 µmol，2.00當量），且將混合物在110℃下放置2小時。將反應混合物冷卻至25℃，倒入水（10.0 mL）中，且用乙酸乙酯（10.0 mL×3）萃取。將合併之有機層用鹽水（10.0 mL）洗滌，經硫酸鈉乾燥，過濾，且在減壓下濃縮。將殘餘物藉由製備型TLC（矽膠板，石油醚/乙酸乙酯＝2/1）純化，且進一步藉由製備型HPLC[管柱：Phenomenex luna C18 150×25 mm×10 um；移動相：A相：水（0.225%甲酸），B相：乙腈，B%：20%-50%]純化，得到呈灰白色固體狀之(R )-6-氟-4-甲基-N -(1-(2-甲基-3-(三氟甲基)苯基)乙基)-7-

啉基呔

-1-胺（4.92 mg，10.7 µmol，7.89%產率，97.6%純度，甲酸鹽）。LCMS [M+1]⁺ : 449.0。Under a nitrogen atmosphere, to ( R )-7-bromo-6-fluoro-4-methyl- N -(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)

-1-amine (60.0 mg, 136 µmol, 1.00 equivalent) in two

Add to the solution in alkane (3.00 mL)

Pd ₂ (dba) ₃ (12.4 mg, 13.6 µmol, 0.10 equivalent) and cesium carbonate (88.4 mg, 271 µmol, 2.00 equivalents), and place the mixture at 110°C for 2 hours. The reaction mixture was cooled to 25°C, poured into water (10.0 mL), and extracted with ethyl acetate (10.0 mL×3). The combined organic layer was washed with brine (10.0 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (silica gel plate, petroleum ether/ethyl acetate = 2/1), and further by preparative HPLC [column: Phenomenex luna C18 150×25 mm×10 um; mobile phase: Phase A: Water (0.225% formic acid), Phase B: Acetonitrile, B%: 20%-50%] Purified to obtain ( R )-6-fluoro-4-methyl- N -(1- (2-Methyl-3-(trifluoromethyl)phenyl)ethyl)-7-

Linyl

-1-amine (4.92 mg, 10.7 µmol, 7.89% yield, 97.6% purity, formate). LCMS [M+1] ⁺ : 449.0.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 8.27 (s, 1H), 7.87 (d, J = 8.4 Hz, 1H), 7.76 (d, J = 7.6 Hz, 1H), 7.71 (d, J = 14.0 Hz, 1H), 7.59 (d, J = 7.2 Hz, 1H), 7.52 (d, J = 7.6 Hz, 1H), 7.32 (t, J = 8.0 Hz, 1H), 5.76-5.61 (m, 1H ), 3.86-3.81 (m, 4H), 3.27-3.23 (m, 4H), 2.58 (s, 3H), 2.54 (s, 3H), 1.56 (d, J = 6.8 Hz, 3H).

SFC conditions: Chiralcel OD-3 50×4.6 mm inner diameter, 3 um; mobile phase: phase A: CO ₂ , phase B: MeOH (0.05% diethylamine); gradient dissociation: MeOH (0.05% diethylamine) In 5% to 40% CO ₂ ; Flow rate: 3 ml/min; Detector: PDA; Column temperature: 35°C; Back pressure: 100 Bar.

(R )-3-(1-((6-氟-4-甲基-7-(4-甲基哌

-1-基)呔

-1-基)胺基)乙基)-2-甲基苯甲腈 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.82 (d,J = 8.5 Hz, 1H), 7.75 (d,J = 7.9 Hz, 1H), 7.67 (d,J = 13.8 Hz, 1H), 7.60 (dd,J = 7.7, 1.3 Hz, 1H), 7.56 (d,J = 6.7 Hz, 1H), 7.31 (t,J = 7.8 Hz, 1H), 5.57 (q,J = 6.9 Hz, 1H), 3.27 - 3.23 (m, 4H), 2.66 (s, 3H), 2.57 - 2.53 (m, 4H), 2.52 (s, 3H), 2.27 (s, 3H), 1.54 (d,J = 7.0 Hz, 3H)。LCMS [M+1]⁺ : 419.3。 18-4

(R )-3-(1-((6-氟-4-甲基-7-(哌

-1-基)呔

-1-基)胺基)乙基)-2-甲基苯甲腈 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.81 (d,J = 8.5 Hz, 1H), 7.75 (d,J = 7.9 Hz, 1H), 7.66 (d,J = 13.7 Hz, 1H), 7.62 - 7.54 (m, 2H), 7.31 (t,J = 7.8 Hz, 1H), 5.62 - 5.53 (m, 1H), 3.29 (s, 3H), 3.19 - 3.11 (m, 4H), 2.94 - 2.88 (m, 4H), 2.67 (s, 3H), 1.54 (d,J = 7.0 Hz, 3H)。LCMS [M+1]⁺ : 405.1。 18-5

(R )-6-氟-4-甲基-N -(1-(2-甲基-3-(三氟甲基)苯基)乙基)-7-(4-甲基哌

-1-基)呔

-1-胺 ¹ H NMR (400 MHz, CD₃ OD) δ 7.84 (d,J = 8.3 Hz, 1H), 7.72 (d,J = 7.8 Hz, 1H), 7.66 (d,J = 13.5 Hz, 1H), 7.49 (d,J = 7.8 Hz, 1H), 7.24 (t,J = 7.8 Hz, 1H), 5.74 (q,J = 6.9 Hz, 1H), 3.33 - 3.31 (m, 4H), 2.74 - 2.69 (m, 4H), 2.62 (s, 3H), 2.60 (s, 3H), 2.42 (s, 3H), 1.64 (d,J = 6.9 Hz, 3H)。LCMS [M+1]⁺ : 462.2。 實例19-1 (R )-3-(1-((7-(3-(二甲基胺基)-3-甲基氮雜環丁烷-1-基)-4-甲基-6-(三氟甲基)呔

-1-基)胺基)乙基)-2-甲基苯甲腈

Following the teaching of General Reaction Scheme III and the method of preparing Example 18-1-18-2, the following compound of formula (I), Example 18-3-18-5, as shown in Table 18, was prepared. Table 18 Example # structure Spectral data 18-3

( R )-3-(1-((6-Fluoro-4-methyl-7-(4-methylpiper

-1-base) 呔

-1-yl)amino)ethyl)-2-methylbenzonitrile ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.82 (d, J = 8.5 Hz, 1H), 7.75 (d, J = 7.9 Hz, 1H), 7.67 (d, J = 13.8 Hz, 1H), 7.60 (dd, J = 7.7, 1.3 Hz, 1H), 7.56 (d, J = 6.7 Hz, 1H), 7.31 (t, J = 7.8 Hz, 1H), 5.57 (q, J = 6.9 Hz, 1H), 3.27 -3.23 (m, 4H), 2.66 (s, 3H), 2.57-2.53 (m, 4H), 2.52 (s, 3H), 2.27 (s, 3H), 1.54 (d, J = 7.0 Hz, 3H). LCMS [M+1] ⁺ : 419.3. 18-4

( R )-3-(1-((6-Fluoro-4-methyl-7-(piper

-1-base) 呔

-1-yl)amino)ethyl)-2-methylbenzonitrile ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.81 (d, J = 8.5 Hz, 1H), 7.75 (d, J = 7.9 Hz, 1H), 7.66 (d, J = 13.7 Hz, 1H), 7.62 -7.54 (m, 2H), 7.31 (t, J = 7.8 Hz, 1H), 5.62-5.53 (m, 1H), 3.29 (s, 3H), 3.19-3.11 (m, 4H), 2.94-2.88 (m , 4H), 2.67 (s, 3H), 1.54 (d, J = 7.0 Hz, 3H). LCMS [M+1] ⁺ : 405.1. 18-5

( R )-6-fluoro-4-methyl- N -(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-7-(4-methylpiper

-1-base) 呔

-1-amine ¹ H NMR (400 MHz, CD ₃ OD) δ 7.84 (d, J = 8.3 Hz, 1H), 7.72 (d, J = 7.8 Hz, 1H), 7.66 (d, J = 13.5 Hz, 1H), 7.49 ( d, J = 7.8 Hz, 1H), 7.24 (t, J = 7.8 Hz, 1H), 5.74 (q, J = 6.9 Hz, 1H), 3.33-3.31 (m, 4H), 2.74-2.69 (m, 4H ), 2.62 (s, 3H), 2.60 (s, 3H), 2.42 (s, 3H), 1.64 (d, J = 6.9 Hz, 3H). LCMS [M+1] ⁺ : 462.2. Example 19-1 ( R )-3-(1-((7-(3-(dimethylamino)-3-methylazetidin-1-yl)-4-methyl-6- (Trifluoromethyl)

-1-yl)amino)ethyl)-2-methylbenzonitrile

Step A: To a solution of methyl 2-amino-4-(trifluoromethyl)benzoate (3.00 g, 13.7 mmol, 1.00 equivalent) in N,N -dimethylformamide (50.0 mL) N- bromosuccinimide (2.68 g, 15.1 mmol, 1.10 equivalents) was added, and the mixture was stirred at 20° C. for 12 hours under a nitrogen atmosphere. The reaction mixture was poured into water (50.0 mL), followed by extraction with ethyl acetate (50.0 mL×3), and the combined organic layer was washed with brine (40.0 mL), dried over sodium sulfate, filtered, and subjected to reduced pressure Down concentrated. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate = 50/1 to 10/1) to obtain 2-amino-5-bromo-4-(trifluoro Methyl (methyl)benzoate (3.30 g, 11.1 mmol, 80.9% yield).

¹ H NMR (400 MHz, DMSO- d ₆ ): δ = 8.06 (s, 1H), 6.93 (s, 1H), 5.86 (s, 2H), 3.84 (s, 3H).

Step B: Add methyl 2-amino-5-bromo-4-(trifluoromethyl)benzoate (3.30 g, 11.1 mmol, 1.00 equivalent) in hydrochloric acid (4.00 M, 100 mL, 36.1 Sodium nitrite (917 mg, 13.3 mmol, 1.20 equivalents) was added to the solution in equivalent), and the mixture was stirred at 0°C for 1 hour under a nitrogen atmosphere. Potassium iodide (3.68 g, 22.1 mmol, 2.00 equivalents) was then added portionwise to the reaction mixture at 0°C, and the mixture was slowly heated to 90°C and stirred under a nitrogen atmosphere for 11 hours. The mixture was cooled to 25°C, extracted with ethyl acetate (100 mL×3), and the combined organic layer was washed with brine (50.0 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate = 100/1 to 20/1) to obtain 5-bromo-2-iodo-4-(trifluoromethyl) as a yellow solid Methyl) benzoate (4.10 g, 10.0 mmol, 90.5% yield).

¹ H NMR (400 MHz, CDCl ₃ ) δ = 8.16 (s, 1H), 8.01 (s, 1H), 3.90 (s, 3H).

Step C: Add methyl 5-bromo-2-iodo-4-(trifluoromethyl)benzoate (3.60 g, 8.80 mmol, 1.00 equivalent) and 1-(vinyloxy)butane (1.06 g, 10.6 mmol, 1.36 mL, 1.20 equivalents) in N,N -dimethylformamide (10.0 mL), add DPPF (244 mg, 440 µmol, 0.05 equivalents), N,N -diethylethylamine ( 2.67 g, 26.4 mmol, 3.68 mL, 3.00 equivalents) and palladium(II) acetate (59.3 mg, 264 µmol, 0.03 equivalents), and the mixture was stirred at 70°C for 12 hours under a nitrogen atmosphere. The mixture was then cooled to 25°C, diluted with tetrahydrofuran (17.8 g, 247 mmol, 20.0 mL, 14.9 equivalents) and hydrochloric acid (4.00 M, 20.0 mL, 4.82 equivalents), and the mixture was stirred at 20°C for 1 hour. The mixture was poured into water (30.0 mL), extracted with ethyl acetate (30.0 mL×3), and the combined organic layer was washed with brine (30.0 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure . The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=50/1 to 10/1) to obtain 2-acetyl-5-bromo-4-(tri Fluoromethyl) methyl benzoate (250 mg, 769 µmol, 8.74% yield).

¹ H NMR (400 MHz, CDCl ₃ ) δ = 8.08 (s, 1H), 7.68 (s, 1H), 3.87 (s, 3H), 2.49 (s, 3H).

-1-醇（170 mg，粗製），其無需進一步純化即可使用。LCMS [M+3]⁺ : 309.1。Step D: Add hydrazine hydrate to a solution of methyl 2-acetyl-5-bromo-4-(trifluoromethyl)benzoate (250 mg, 769 µmol, 1.00 equivalent) in ethanol (5.00 mL) (46.2 mg, 923 µmol, 44.8 µL, 98%, 1.20 equivalents), and the mixture was stirred at 95°C for 30 minutes under a nitrogen atmosphere. The mixture was cooled to 25°C and concentrated under reduced pressure to obtain 7-bromo-4-methyl-6-(trifluoromethyl) as a yellow solid

-1-ol (170 mg, crude), which can be used without further purification. LCMS [M+3] ⁺ : 309.1.

-1-醇（50.0 mg，162.8 µmol，1.00當量）於POCl₃ （4.95 g，32.3 mmol，3.00 mL，198當量）中之溶液在氮氣氛圍下在110℃下攪拌1小時。將混合物冷卻至25℃，用乙酸乙酯（50.0 mL）稀釋，隨後藉由添加飽和碳酸氫鈉（水溶液，50.0 mL）來淬滅。將溶液用乙酸乙酯（50.0 mL×3）萃取，且將合併之有機層用鹽水（40.0 mL）洗滌，經硫酸鈉乾燥，過濾，且在減壓下濃縮，得到殘餘物。將殘餘物藉由製備型TLC（矽膠板，石油醚/乙酸乙酯=1/1）純化，得到呈褐色油狀之6-溴-4-氯-1-甲基-7-(三氟甲基)呔

（20.0 mg，61.4 µmol，37.7%產率）。LCMS [M+3]⁺ : 326.7。Step E: Add 7-bromo-4-methyl-6-(trifluoromethyl)

A solution of -1-ol (50.0 mg, 162.8 µmol, 1.00 equivalent) in POCl ₃ (4.95 g, 32.3 mmol, 3.00 mL, 198 equivalents) was stirred at 110°C for 1 hour under a nitrogen atmosphere. The mixture was cooled to 25°C, diluted with ethyl acetate (50.0 mL), and then quenched by the addition of saturated sodium bicarbonate (aqueous solution, 50.0 mL). The solution was extracted with ethyl acetate (50.0 mL×3), and the combined organic layer was washed with brine (40.0 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by preparative TLC (silica gel plate, petroleum ether/ethyl acetate=1/1) to obtain 6-bromo-4-chloro-1-methyl-7-(trifluoromethyl) as a brown oil Base) eh

(20.0 mg, 61.4 µmol, 37.7% yield). LCMS [M+3] ⁺ : 326.7.

（120 mg，369 µmol，1.00當量）及(R )-3-(1-胺基乙基)-2-甲基苯甲腈（59.0 mg，369 µmol，1.00當量）於二甲基亞碸（3.00 mL）中之溶液中添加氟化鉀（107 mg，1.84 mmol，43.2 µL，5.00當量），且將反應在氮氣氛圍下在130℃下攪拌12小時。將反應混合物冷卻至25℃，倒入水（10.0 mL）中，且用乙酸乙酯（10.0 mL×3）萃取。將合併之有機層用鹽水（10.0 mL）洗滌，經硫酸鈉乾燥，過濾，且在減壓下濃縮。將殘餘物藉由製備型TLC（矽膠板，二氯甲烷/甲醇＝10/1）純化，得到呈淺黃色固體狀之(R )-3-(1-((7-溴-4-甲基-6-(三氟甲基)呔

-1-基)胺基)乙基)-2-甲基苯甲腈（110 mg，244 µmol，產率66.4%）。 LCMS [M+3]⁺ : 451.2。Step F: To-bromo-4-chloro-1-methyl-7-(trifluoromethyl)

(120 mg, 369 µmol, 1.00 equivalent) and ( R )-3-(1-aminoethyl)-2-methylbenzonitrile (59.0 mg, 369 µmol, 1.00 equivalent) in dimethyl sulfoxide ( 3.00 mL) potassium fluoride (107 mg, 1.84 mmol, 43.2 µL, 5.00 equivalents) was added to the solution in 3.00 mL), and the reaction was stirred at 130°C for 12 hours under a nitrogen atmosphere. The reaction mixture was cooled to 25°C, poured into water (10.0 mL), and extracted with ethyl acetate (10.0 mL×3). The combined organic layer was washed with brine (10.0 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (silica gel plate, dichloromethane/methanol=10/1) to obtain ( R )-3-(1-((7-bromo-4-methyl) as a pale yellow solid -6-(Trifluoromethyl)

-1-yl)amino)ethyl)-2-methylbenzonitrile (110 mg, 244 µmol, yield 66.4%). LCMS [M+3] ⁺ : 451.2.

-1-基)胺基)乙基)-2-甲基苯甲腈（30.0 mg，0.07 mmol，1.00當量）及N,N ,3-三甲基氮雜環丁烷-3-胺（20.0 mg，0.13 mmol，2.00當量，HCl鹽）於二

烷（2.00 mL）中之溶液中添加Pd₂ (dba)₃ （6.00 mg，0.10當量）、RuPhos（6.00 mg，0.20當量）及碳酸銫（108 mg，0.33 mmol，5.00當量），將其在氮氣氛圍下在100℃下攪拌12小時。將反應混合物冷卻至25℃，藉由添加水（20.0 mL）來淬滅，且用乙酸乙酯（20.0 mL×3）萃取。將合併之有機層用鹽水（20.0 mL×3）洗滌，經硫酸鈉乾燥，過濾，且在減壓下濃縮。將殘餘物藉由製備型HPLC[管柱：Waters xbridge 150×25 mm×10 um；移動相：A相：水（10 mM NH₄ HCO₃ ），B相：乙腈；B%：38%-68%]純化，得到呈黃色固體狀之(R )-3-(1-((7-(3-(二甲基胺基)-3-甲基氮雜環丁烷-1-基)-4-甲基-6-(三氟甲基)呔

-1-基)胺基)乙基)-2-甲基苯甲腈（3.28 mg，9.91%產率，97.4%純度）。LCMS [M+1]⁺ : 483.4。Step G: To ( R )-3-(1-((7-bromo-4-methyl-6-(trifluoromethyl)

-1-yl)amino)ethyl)-2-methylbenzonitrile (30.0 mg, 0.07 mmol, 1.00 equivalent) and N,N ,3-trimethylazetidine-3-amine (20.0 mg, 0.13 mmol, 2.00 equivalents, HCl salt) in two

_{Add Pd 2} (dba) ₃ (6.00 mg, 0.10 equivalent), RuPhos (6.00 mg, 0.20 equivalent) and cesium carbonate (108 mg, 0.33 mmol, 5.00 equivalent) to the solution in alkane (2.00 mL), and put it under nitrogen Stir at 100°C for 12 hours under the atmosphere. The reaction mixture was cooled to 25°C, quenched by adding water (20.0 mL), and extracted with ethyl acetate (20.0 mL×3). The combined organic layer was washed with brine (20.0 mL×3), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to preparative HPLC [column: Waters xbridge 150×25 mm×10 um; mobile phase: phase A: water (10 mM NH ₄ HCO ₃ ), phase B: acetonitrile; B%: 38%-68 %] was purified to obtain ( R )-3-(1-((7-(3-(dimethylamino)-3-methylazetidin-1-yl)-4 as a yellow solid -Methyl-6-(trifluoromethyl)

-1-yl)amino)ethyl)-2-methylbenzonitrile (3.28 mg, 9.91% yield, 97.4% purity). LCMS [M+1] ⁺ : 483.4.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 8.06 (s, 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.60 (d, J = 7.2 Hz, 1H), 7.51 (d, J = 6.8 Hz, 1H), 7.30 (t, J = 7.6 Hz, 1H), 7.24 (s, 1H), 5.58-5.53 (m, 1H), 4.00-3.95 (m, 2H), 3.90-3.86 (m, 2H), 2.66 (s, 3H), 2.55 (s, 3H), 2.16 (s, 6H), 1.56 (d, J = 7.2 Hz, 3H), 1.33 (s, 3H).

啉基-6-(三氟甲基)呔

-1-基)胺基)乙基)苯甲腈

SFC conditions: column: Chiralpak AS-3 50×4.6 mm inner diameter, 3 um; mobile phase: phase A: CO ₂ , phase B: MeOH (0.05% diethylamine); gradient dissolution: MeOH (0.05% diethylamine) Amine) in 5% to 40% CO ₂ ; flow rate: 3 ml/min; detector: PDA; column temperature: 35°C; back pressure: 100 Bar. Example 19-2 ( R )-2-methyl-3-(1-((4-methyl-7-

Linyl-6-(trifluoromethyl)

-1-yl)amino)ethyl)benzonitrile

-1-基)胺基)乙基)-2-甲基苯甲腈（40.0 mg，89.0 µmol，1.00當量）及

啉（22.0 mg，178 µmol，22.2 µL，2.00當量）於二

烷（3.00 mL）中之溶液中添加碳酸銫（58.0 mg，178 µmol，2.00當量）、Pd₂ (dba)₃ （8.15 mg，8.90 µmol，0.10當量）及RuPhos（8.31 mg，17.8 µmol，0.20當量），且將反應混合物在105℃下攪拌12小時。隨後將混合物冷卻至25℃，倒入水（30.0 mL）中，且用乙酸乙酯（30.0 mL×3）萃取。將合併之有機層用水（20.0 mL）洗滌，經硫酸鈉乾燥，過濾，且在減壓下濃縮。將殘餘物藉由製備型HPLC[管柱：Waters xbridge 150×25 mm 10 um；移動相：A相：水（10 mM NH₄ HCO₃ ），B相：乙腈；B%：37%-67%]純化，得到呈色固體狀之(R )-2-甲基-3-(1-((4-甲基-7-

啉基-6-(三氟甲基)呔

-1-基)胺基)乙基)苯甲腈（2.57 mg，5.33 µmol，5.99%產率，94.5%純度）。LCMS [M+1]⁺ : 456.3。In a nitrogen atmosphere, to ( R )-3-(1-((7-bromo-4-methyl-6-(trifluoromethyl)

-1-yl)amino)ethyl)-2-methylbenzonitrile (40.0 mg, 89.0 µmol, 1.00 equivalent) and

Morpholine (22.0 mg, 178 µmol, 22.2 µL, 2.00 equivalent) in two

Add cesium carbonate (58.0 mg, 178 µmol, 2.00 equivalents), Pd ₂ (dba) ₃ (8.15 mg, 8.90 µmol, 0.10 equivalents) and RuPhos (8.31 mg, 17.8 µmol, 0.20 equivalents) to the solution in alkane (3.00 mL) ), and the reaction mixture was stirred at 105°C for 12 hours. The mixture was then cooled to 25°C, poured into water (30.0 mL), and extracted with ethyl acetate (30.0 mL×3). The combined organic layer was washed with water (20.0 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to preparative HPLC [column: Waters xbridge 150×25 mm 10 um; mobile phase: phase A: water (10 mM NH ₄ HCO ₃ ), phase B: acetonitrile; B%: 37%-67% ] Purification to obtain ( R )-2-methyl-3-(1-((4-methyl-7-

Linyl-6-(trifluoromethyl)

-1-yl)amino)ethyl)benzonitrile (2.57 mg, 5.33 µmol, 5.99% yield, 94.5% purity). LCMS [M+1] ⁺ : 456.3.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 8.58 (s, 1H), 8.22 (s, 1H), 7.83 (d, J = 6.4 Hz, 1H), 7.75 (d, J = 7.6 Hz, 1H ), 7.62 (d, J = 7.2 Hz, 1H), 7.33 (t, J = 7.2 Hz, 1H), 5.63-5.54 (m, 1H), 3.83-3.78 (m, 4H), 3.10-3.05 (m, 4H), 2.68 (s, 3H), 2.66 (s, 3H), 1.58 (d, J = 7.2 Hz, 3H).

SFC conditions: column: Chiralpak AS-3 50×4.6mm inner diameter, 3 um; mobile phase: phase A: CO ₂ , phase B: MeOH (0.05% diethylamine); gradient dissolution: MeOH (0.05% diethyl) Amine) in 5% to 40% CO ₂ ; flow rate: 3 ml/min; detector: PDA; column temperature: 35°C; back pressure: 100 Bar.

(R )-3-(1-((7-(3-羥基-3-甲基氮雜環丁烷-1-基)-4-甲基-6-(三氟甲基)呔

-1-基)胺基)乙基)-2-甲基苯甲腈 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.06 (s, 1H), 7.74 (d,J = 7.8 Hz, 1H), 7.60 (d,J = 7.6 Hz, 1H), 7.54 (d,J = 6.8 Hz, 1H), 7.31 (t,J = 7.8 Hz, 1H), 7.23 (s, 1H), 5.69 (s, 1H), 5.60 - 5.52 (m, 1H), 4.11 - 4.00 (m, 4H), 3.30 (s, 5H), 2.66 (s, 3H), 2.55 (s, 3H), 2.33 (d,J = 1.9 Hz, 1H), 1.55 (d,J = 7.0 Hz, 3H), 1.51 (s, 3H)。LCMS [M+1]⁺ : 456.4。 實例20-1 1-(3-((R )-1-((7-((1R ,4R )-2-氧雜-5-氮雜雙環[2.2.1]庚-5-基)-4-甲基吡啶并[3,4-d ]嗒

-1-基)胺基)乙基)-2-氟苯基)-1,1-二氟-2-甲基丙-2-醇

Following the teaching of General Reaction Scheme IV and the method of preparing Examples 19-1-19-2, the following compounds of formula (I), Example 19-3, as shown in Table 19, were prepared. Table 19 Example # structure Spectral data 19-3

( R )-3-(1-((7-(3-hydroxy-3-methylazetidin-1-yl)-4-methyl-6-(trifluoromethyl)

-1-yl)amino)ethyl)-2-methylbenzonitrile ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.06 (s, 1H), 7.74 (d, J = 7.8 Hz, 1H), 7.60 (d, J = 7.6 Hz, 1H), 7.54 (d, J = 6.8 Hz, 1H), 7.31 (t, J = 7.8 Hz, 1H), 7.23 (s, 1H), 5.69 (s, 1H), 5.60-5.52 (m, 1H), 4.11-4.00 (m, 4H), 3.30 (s, 5H), 2.66 (s, 3H), 2.55 (s, 3H), 2.33 (d, J = 1.9 Hz, 1H), 1.55 (d, J = 7.0 Hz, 3H), 1.51 (s, 3H ). LCMS [M+1] ⁺ : 456.4. Example 20-1 1-(3-(( R )-1-((7-((1 R ,4 R )-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl) -4-methylpyrido[3,4- d ]

-1-yl)amino)ethyl)-2-fluorophenyl)-1,1-difluoro-2-methylpropan-2-ol

Step A: Add 1-bromo-2-fluoro-3-iodobenzene (4.00 g, 13.3 mmol, 1.00 equivalent) and ethyl 2-bromo-2,2-difluoroacetate (3.80 g, 18.6 mmol, 2.40 mL, 1.40 equivalents) Copper (2.53 g, 39.9 mmol, 3.00 equivalents) was added to a solution in dimethyl sulfoxide (50.0 mL), and the mixture was stirred at 70°C for 12 hours. The reaction mixture was cooled to 25°C, quenched by adding water (100 mL), and extracted with ethyl acetate (200 mL×3). The combined organic layer was washed with brine (100 mL×3), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate = 10/1 to 5/1) to obtain 2-(3-bromo-2-fluorophenyl)- as a yellow oil Ethyl 2,2-difluoroacetate (2.00 g, 6.73 mmol, 50.6% yield).

¹ H NMR (400 MHz, CDCl ₃ ) δ = 7.72-7.69 (m, 1H), 7.61-7.57 (m, 1H), 7.15 (t, J = 8.0 Hz, 1H), 4.39-4.34 (m, 2H) , 1.35-1.32 (m, 3H).

Step B: Add 2-(3-bromo-2-fluorophenyl)-2,2-difluoroethyl acetate (2.00 g, 6.73 mmol, 1.00 equivalent) in tetrahydrofuran (30.0 mL) at 0°C To the solution was added methylmagnesium bromide solution (3.00 M, 6.75 mL, 3.00 equivalents), and the mixture was stirred at 0°C for 2 hours. The mixture was then heated to 25°C, diluted with water (10.0 mL), and extracted with ethyl acetate (20.0 mL×3). The combined organic layer was washed with brine (20.0 mL×3), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate = 10/1 to 3/1) to obtain 1-(3-bromo-2-fluorophenyl)- as a yellow oil 1,1-Difluoro-2-methylpropan-2-ol (1.70 g, 6.01 mmol, 89.2% yield).

¹ H NMR (400 MHz, CDCl ₃ ) δ = 7.67-7.65 (m, 1H), 7.43-7.39 (m, 1H), 7.12-7.09 (m, 1H), 1.35 (d, J = 0.8 Hz, 6H) .

烷（15.0 mL）中之溶液中添加PdCl₂ (PPh₃ )₂ （380 mg，0.53 mmol，0.10當量），且將混合物在氮氣氛圍下在80℃下攪拌12小時。隨後將反應混合物冷卻至25℃，用飽和氟化鉀溶液（100 mL）稀釋，且用乙酸乙酯（200 mL×3）萃取。將合併之有機層用鹽水（200 mL×3）洗滌，經硫酸鈉乾燥，過濾，且在減壓下濃縮，得到呈黑色油狀之1-(3-(1-乙氧基乙烯基)-2-氟苯基)-1,1-二氟-2-甲基丙-2-醇（2.00 g，粗製）。向1-(3-(1-乙氧基乙烯基)-2-氟苯基)-1,1-二氟-2-甲基丙-2-醇（2.00 g，7.29 mmol，1.00當量）於四氫呋喃（20.0 mL）中之溶液添加鹽酸鹽（4.00 M，10.0 mL），且將混合物在25℃下攪拌1小時。將反應混合物藉由添加水（100 mL）來淬滅，且用乙酸乙酯（200 mL×3）萃取。將合併之有機層用鹽水（200 mL×3）洗滌，經硫酸鈉乾燥，過濾，且在減壓下濃縮。將殘餘物藉由管柱層析法（矽膠，石油醚/乙酸乙酯＝10/1至1/1）純化，得到呈黃色油狀之1-(3-(1,1-二氟-2-羥基-2-甲基丙基)-2-氟苯基)乙-1-酮（1.50 g，6.09 mmol，83.5%產率）。Step C: Add 1-(3-bromo-2-fluorophenyl)-1,1-difluoro-2-methylpropan-2-ol (1.50 g, 5.30 mmol, 1.00 equivalent) and tributyl (1 -Ethoxy vinyl) tin (3.83 g, 10.6 mmol, 3.58 mL, 2.00 equivalents) in 1,4-di

_{PdCl 2} (PPh ₃ ) ₂ (380 mg, 0.53 mmol, 0.10 equivalent) was added to the solution in alkane (15.0 mL), and the mixture was stirred at 80° C. for 12 hours under a nitrogen atmosphere. The reaction mixture was then cooled to 25°C, diluted with saturated potassium fluoride solution (100 mL), and extracted with ethyl acetate (200 mL×3). The combined organic layer was washed with brine (200 mL×3), dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain 1-(3-(1-ethoxyvinyl)- as a black oil 2-fluorophenyl)-1,1-difluoro-2-methylpropan-2-ol (2.00 g, crude). To 1-(3-(1-ethoxyvinyl)-2-fluorophenyl)-1,1-difluoro-2-methylpropan-2-ol (2.00 g, 7.29 mmol, 1.00 equivalent) in The solution in tetrahydrofuran (20.0 mL) was added with hydrochloride (4.00 M, 10.0 mL), and the mixture was stirred at 25°C for 1 hour. The reaction mixture was quenched by adding water (100 mL), and extracted with ethyl acetate (200 mL×3). The combined organic layer was washed with brine (200 mL×3), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate = 10/1 to 1/1) to obtain 1-(3-(1,1-difluoro-2) as a yellow oil -Hydroxy-2-methylpropyl)-2-fluorophenyl)ethan-1-one (1.50 g, 6.09 mmol, 83.5% yield).

¹ H NMR (400 MHz, CDCl ₃ ) δ = 7.97-7.91 (m, 1H), 7.66-7.61 (m, 1H), 7.31-7.27 (m, 1H), 2.66 (d, J = 4.0 Hz, 3H) , 1.37 (d, J = 1.2 Hz, 6H).

Step D: To 1-(3-(1,1-difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethan-1-one (1.50 g, 6.09 mmol, 1.00 equivalent) And ( R )-2-methylpropane-2-sulfinamide (2.22 g, 18.3 mmol, 3.00 equivalents) in tetrahydrofuran (10.0 mL) was added titanium (IV) isopropoxide (3.46 g, 12.2 mmol, 3.60 mL, 2.00 equivalents) and 1-methoxy-2-(2-methoxyethoxy)ethane (1.63 g, 12.2 mmol, 1.74 mL, 2.00 equivalents), and the mixture was placed under a nitrogen atmosphere Stir at 70°C for 6 hours. The mixture was then cooled to 25°C, diluted with water (50.0 mL) and extracted with ethyl acetate (50.0 mL×3). The combined organic layer was washed with brine (50.0 mL×3), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate = 10/1 to 1/1) to obtain ( R ) -N -(1-(3-(1) as a yellow oil ,1-Difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethylene)-2-methylpropane-2-sulfinamide (1.50 g, 4.29 mmol, 70.1% Yield).

¹ H NMR (400 MHz, CDCl ₃ ) δ = 7.73-7.68 (m, 1H), 7.60-7.52 (m, 1H), 7.26-7.22 (m, 1H), 1.37-1.35 (m, 3H), 1.32 ( s, 6H), 1.24 (s, 9H)

Step E: Ethylene (R ) -N -(1-(3-(1,1-difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl) at 0°C )-2-Methylpropane-2-sulfinamide (1.50 g, 4.29 mmol, 1.00 equivalent) in tetrahydrofuran (10.0 mL) was slowly added sodium borohydride (488 mg, 12.9 mmol, 3.00 equivalent), And the mixture was stirred at 0°C for 12 hours. The mixture was then diluted with water (50.0 mL), and extracted with ethyl acetate (100 mL×3). The combined organic layer was washed with brine (50.0 mL×3), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate = 10/1 to 1/1) to obtain ( R ) -N -(1-(3-(1) as a yellow oil ,1-Difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethyl)-2-methylpropane-2-sulfinamide (1.30 g, 3.70 mmol, 86.2% yield Rate).

¹ H NMR (400 MHz, CDCl ₃ ) δ = 7.45-7.27 (m, 2H), 7.16-7.10 (m, 1H), 4.60 -4.55 (m, 1H), 3.66-3.58 (m, 1H), 1.30- 1.26 (m, 3H), 1.16 (s, 6H), 1.14-1.10 (m, 9H).

Step F: To ( R ) -N -(1-(3-(1,1-difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethyl)-2-methyl To a solution of propane-2-sulfinamide (600 mg, 1.71 mmol, 1.00 equivalent) in dichloromethane (5.00 mL) was added hydrochloride (4.00 M, 5.00 mL), and the mixture was stirred at 25°C 30 minutes. The mixture was then concentrated under reduced pressure to obtain 1-(3-(1-aminoethyl)-2-fluorophenyl)-1,1-difluoro-2-methylpropan-2 as a yellow oil -Alcohol (400 mg, 1.41 mmol, 82.3% yield, hydrochloride).

（175 mg，0.81 mmol，1.00當量）於二甲基亞碸（2.00 mL）中之溶液中添加氟化鉀（235 mg，4.04 mmol，5.00當量），且將混合物在130℃下攪拌12小時。隨後將混合物冷卻至25℃，用水（10.0 mL）稀釋， 且用乙酸乙酯（10.0 mL×3）萃取。將合併之有機層用鹽水（10.0 mL）洗滌，經硫酸鈉乾燥，過濾，且在減壓下濃縮。將殘餘物藉由製備型HPLC[管柱：Welch Xtimate C18 150×25 mm×5 um；移動相：A相：水（0.05% HCl），B相：乙腈；B%：14%-44%]純化，得到呈黃色固體狀之1-(3-(1-((7-氯-4-甲基吡啶并[3,4-d ]嗒

-1-基)胺基)乙基)-2-氟苯基)-1,1-二氟-2-甲基丙-2-醇（140 mg，321 µmol，39.7%產率，97.5%純度）。LCMS [M+1]⁺ : 425.0。Step G: To 1-(3-(1-aminoethyl)-2-fluorophenyl)-1,1-difluoro-2-methylpropan-2-ol (200 mg, 0.81 mmol, 1.00 equivalent ) And 1,7-dichloro-4-methylpyrido[3,4-d]

(175 mg, 0.81 mmol, 1.00 equivalent) Potassium fluoride (235 mg, 4.04 mmol, 5.00 equivalent) was added to a solution in dimethyl sulfoxide (2.00 mL), and the mixture was stirred at 130°C for 12 hours. The mixture was then cooled to 25°C, diluted with water (10.0 mL) , and extracted with ethyl acetate (10.0 mL×3). The combined organic layer was washed with brine (10.0 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to preparative HPLC [column: Welch Xtimate C18 150×25 mm×5 um; mobile phase: phase A: water (0.05% HCl), phase B: acetonitrile; B%: 14%-44%] Purified to obtain 1-(3-(1-((7-chloro-4-methylpyrido[3,4- d ]

-1-yl)amino)ethyl)-2-fluorophenyl)-1,1-difluoro-2-methylpropan-2-ol (140 mg, 321 µmol, 39.7% yield, 97.5% purity ). LCMS [M+1] ⁺ : 425.0.

-1-基)胺基]乙基]-2-氟-苯基]-1,1-二氟-2-甲基-丙-2-醇（140 mg，330 µmol，1.00當量）分離為兩種鏡像異構體，經由SFC[管柱：REGIS(S,S)WHELK-O1（250 mm×25 mm，10 um）；移動相：A相：0.1% NH₄ OH於IPA中，B相：CO₂ ；B%：55%-55%]純化，得到呈黃色固體狀之(R )-1-(3-(1-((7-氯-4-甲基吡啶并[3,4-d]嗒

-1-基)胺基)乙基)-2-氟苯基)-1,1-二氟-2-甲基丙-2-醇（第一溶離異構體，70.0 mg，0.16 mmol，50.0%產率）。Step H: The solid 1-[3-[1-[(7-chloro-4-methyl-pyrido[3,4- d ]

-1-yl)amino]ethyl]-2-fluoro-phenyl]-1,1-difluoro-2-methyl-propan-2-ol (140 mg, 330 µmol, 1.00 equivalent) separated into two Spiegelmer, through SFC[Column: REGIS(S,S)WHELK-O1 (250 mm×25 mm, 10 um); mobile phase: A phase: 0.1% NH ₄ OH in IPA, B phase: CO ₂ ; B%: 55%-55%] was purified to obtain ( R )-1-(3-(1-((7-chloro-4-methylpyrido[3,4-d ]despair

-1-yl)amino)ethyl)-2-fluorophenyl)-1,1-difluoro-2-methylpropan-2-ol (first lysomer, 70.0 mg, 0.16 mmol, 50.0 %Yield).

SFC characterization: column: ( S, S ) Whelk-O1 50×4.6 mm inner diameter, 1.8 um; mobile phase: phase A: CO ₂ , phase B: IPA (0.05% diethylamine); gradient dissolution: 40 % IPA (0.05% diethylamine) in CO ₂ ; flow rate: 3 ml/min; detector: PDA; column temperature: 35°C; back pressure: 100 Bar.

-1-基)胺基)乙基)-2-氟苯基)-1,1-二氟-2-甲基丙-2-醇（20.0 mg，0.05 mmol，1.00當量）及(1R,4R)-2-氧雜-5-氮雜雙環[2.2.1]庚烷（12.8 mg，0.09 mmol，2.00當量，鹽酸鹽）於1,4-二

烷（1.50 mL）中之溶液中添加Pd₂ (dba)₃ （4.31 mg，4.71 µmol，0.10當量）、RuPhos（4.39 mg，9.42 µmol，0.20當量）及碳酸銫（76.8 mg，0.24 mmol，5.00當量），且將混合物在氮氣氛圍下在100℃下攪拌12小時。將混合物冷卻至25℃，用水（10.0 mL）稀釋，且用乙酸乙酯（20.0 mL×3）萃取。將合併之有機層用鹽水（20.0 mL）洗滌，經硫酸鈉乾燥，過濾，且在減壓下濃縮。將殘餘物藉由製備型HPLC[管柱：Waters xbridge 150×25 mm 10 um；移動相：A相：水（10 mM NH₄ HCO₃ ），B相：乙腈； B%：20%-50%]純化，得到呈黃色固體狀之1-(3-((R )-1-((7-((1R ,4R )-2-氧雜-5-氮雜雙環[2.2.1]庚-5-基)-4-甲基吡啶并[3,4-d ]嗒

-1-基)胺基)乙基)-2-氟苯基)-1,1-二氟-2-甲基丙-2-醇（11.4 mg，0.02 mmol，48.6%產率，97.6%純度）。LCMS [M+1]⁺ : 488.3。Step I: To ( R )-1-(3-(1-((7-chloro-4-methylpyrido[3,4-d]

-1-yl)amino)ethyl)-2-fluorophenyl)-1,1-difluoro-2-methylpropan-2-ol (20.0 mg, 0.05 mmol, 1.00 equivalent) and (1R,4R )-2-oxa-5-azabicyclo[2.2.1]heptane (12.8 mg, 0.09 mmol, 2.00 equivalents, hydrochloride) in 1,4-bis

_{Add Pd 2} (dba) ₃ (4.31 mg, 4.71 µmol, 0.10 equivalent), RuPhos (4.39 mg, 9.42 µmol, 0.20 equivalent) and cesium carbonate (76.8 mg, 0.24 mmol, 5.00 equivalent) to the solution in alkane (1.50 mL) ), and the mixture was stirred at 100°C for 12 hours under a nitrogen atmosphere. The mixture was cooled to 25°C, diluted with water (10.0 mL), and extracted with ethyl acetate (20.0 mL×3). The combined organic layer was washed with brine (20.0 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to preparative HPLC [column: Waters xbridge 150×25 mm 10 um; mobile phase: phase A: water (10 mM NH ₄ HCO ₃ ), phase B: acetonitrile; B%: 20%-50% ] Purification to obtain 1-(3-(( R )-1-((7-((1 R ,4 R )-2-oxa-5-azabicyclo[2.2.1]heptan as a yellow solid -5-yl)-4-methylpyrido[3,4- d ]

-1-yl)amino)ethyl)-2-fluorophenyl)-1,1-difluoro-2-methylpropan-2-ol (11.4 mg, 0.02 mmol, 48.6% yield, 97.6% purity ). LCMS [M+1] ⁺ : 488.3.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 8.97 (s, 1H), 7.51-7.46 (m, 1H), 7.36 (d, J = 8.0 Hz, 1H), 7.30-7.26 (m, 1H) , 7.20-7.14 (m, 2H), 5.72-5.63 (m, 1H), 5.34 (s, 1H), 5.08 (s, 1H), 4.78 (s, 1H), 3.88 (d, J = 8.0 Hz, 1H ), 3.72 (d, J = 8.0 Hz, 1H), 3.62 (d, J = 12.0 Hz, 1H), 3.40 (d, J = 8.0 Hz, 1H), 2.55 (s, 3H), 2.02-1.93 (m , 2H), 1.58 (d, J = 4.0 Hz, 3H), 1.22 (d, J = 4.0 Hz, 6H).

SFC conditions: column: Chiralpak AS-3 50×4.6 mm inner diameter, 3 um; mobile phase: phase A: CO ₂ , phase B: MeOH (0.05% diethylamine); gradient dissolution: MeOH (0.05% diethyl) Amine) in 5% to 40% CO ₂ ; flow rate: 3 ml/min; detector: PDA; column temperature: 35°C; back pressure: 100 Bar.

1,1-二氟-1-(2-氟-3-((R )-1-((7-((S )-六氫吡

并[2,1-c ][1,4]

-8(1H )-基)-4-甲基吡啶并[3,4-d ]嗒

-1-基)胺基)乙基)苯基)-2-甲基丙-2-醇 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.00 (s, 1H), 7.49 (t,J = 7.1 Hz, 1H), 7.46 - 7.41 (m, 2H), 7.29 (t,J = 7.2 Hz, 1H), 7.16 (t,J = 7.7 Hz, 1H), 5.71 - 5.63 (m, 1H), 5.35 (s, 1H), 4.46 (d,J = 12.6 Hz, 1H), 4.39 (d,J = 12.3 Hz, 1H), 3.87 - 3.77 (m, 2H), 3.64 - 3.54 (m, 1H), 3.28 - 3.21 (m, 1H), 3.14 - 3.04 (m, 1H), 2.93 (d,J = 11.4 Hz, 1H), 2.78 - 2.70 (m, 1H), 2.65 - 2.58 (m, 1H), 2.57 (s, 3H), 2.32 - 2.17 (m, 2H), 1.59 (d,J = 7.0 Hz, 3H), 1.24 (s, 4H), 1.23 (s, 3H)。LCMS [M+1]⁺ : 531.3。 20-3

1-(3-((1R)-1-((7-(6-氧雜-3-氮雜雙環[3.1.1]庚-3-基)-4-甲基吡啶并[3,4-d]嗒

-1-基)胺基)乙基)-2-氟苯基)-1,1-二氟-2-甲基丙-2-醇 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.06 (s, 1H), 7.56 - 7.47 (m, 2H), 7.32 - 7.25 (m, 2H), 7.16 (t,J = 7.7 Hz, 1H), 5.75 - 5.67 (m, 1H), 5.35 (s, 1H), 4.82 (d,J = 6.4 Hz, 2H), 3.96 - 3.87 (m, 2H), 3.78 - 3.68 (m, 2H), 3.24 - 3.16 (m, 1H), 2.59 (s, 3H), 1.96 (d,J = 8.8 Hz, 1H), 1.59 (d,J = 7.0 Hz, 3H), 1.24 (s, 3H), 1.23 (s, 3H)。LCMS [M+1]⁺ : 488.4。 實例21-1 (R )-3-(1-((4-甲基-7-

啉基吡啶并[3,4-d ]嗒

-1-基)胺基)乙基)-5-(三氟甲基)苯酚

Following the teaching of General Reaction Scheme III and the method of preparing Example 20-1, the following compound of formula (I) as shown in Table 20, Example 20-2-20-3, was prepared. Table 20 Example # structure Spectral data 20-2

1,1-Difluoro-1-(2-fluoro-3-(( R )-1-((7-(( S )-hexahydropyridine

And [2,1- c ][1,4]

-8(1 H )-yl)-4-methylpyrido[3,4- d ]

-1-yl)amino)ethyl)phenyl)-2-methylpropan-2-ol ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.00 (s, 1H), 7.49 (t, J = 7.1 Hz, 1H), 7.46-7.41 (m, 2H), 7.29 (t, J = 7.2 Hz, 1H), 7.16 (t, J = 7.7 Hz, 1H), 5.71-5.63 (m, 1H), 5.35 (s, 1H), 4.46 (d, J = 12.6 Hz, 1H), 4.39 (d, J = 12.3 Hz, 1H), 3.87-3.77 (m, 2H), 3.64-3.54 (m, 1H), 3.28-3.21 (m, 1H), 3.14-3.04 (m, 1H), 2.93 (d, J = 11.4 Hz, 1H), 2.78-2.70 (m, 1H), 2.65-2.58 (m, 1H), 2.57 (s, 3H), 2.32-2.17 (m, 2H), 1.59 (d, J = 7.0 Hz, 3H), 1.24 (s, 4H), 1.23 (s, 3H). LCMS [M+1] ⁺ : 531.3. 20-3

1-(3-((1R)-1-((7-(6-oxa-3-azabicyclo[3.1.1]hept-3-yl)-4-methylpyrido[3,4- d]

-1-yl)amino)ethyl)-2-fluorophenyl)-1,1-difluoro-2-methylpropan-2-ol ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.06 (s, 1H), 7.56-7.47 (m, 2H), 7.32-7.25 (m, 2H), 7.16 (t, J = 7.7 Hz, 1H), 5.75-5.67 (m, 1H), 5.35 (s, 1H), 4.82 (d, J = 6.4 Hz, 2H), 3.96-3.87 (m, 2H), 3.78-3.68 (m, 2H), 3.24-3.16 ( m, 1H), 2.59 (s, 3H), 1.96 (d, J = 8.8 Hz, 1H), 1.59 (d, J = 7.0 Hz, 3H), 1.24 (s, 3H), 1.23 (s, 3H). LCMS [M+1] ⁺ : 488.4. Example 21-1 ( R )-3-(1-((4-methyl-7-

Hydroxypyrido[3,4- d ]

-1-yl)amino)ethyl)-5-(trifluoromethyl)phenol

-7-基)

啉（100 mg，378 µmol，1.00當量）於二甲基亞碸（3.00 mL）中之溶液中添加氟化鉀（87.8 mg，1.51 mmol，35.4 µL，4.00當量），將溶液在130℃下攪拌12小時。將反應混合物為用水（15.0 mL）稀釋，用乙酸乙酯（10.0 mL×3）萃取，用鹽水（5.00 mL×3）洗滌，經無水硫酸鈉乾燥，過濾，且在減壓下濃縮，得到殘餘物。將殘餘物藉由製備型TLC（二氯甲烷/甲醇＝10/1）純化，得到呈黃色固體狀之(R )-N -(1-(3-(苯甲氧基)-5-(三氟甲基)苯基)乙基)-4-甲基-7-

啉基吡啶并[3,4-d ]嗒

-1-胺（65.0 mg，121 µmol，32.1%產率，97.8%純度）。LCMS [M+1]⁺ : 524.3。Step A: Under nitrogen atmosphere, to (R)-1-(3-(benzyloxy)-5-(trifluoromethyl)phenyl)ethan-1-amine (120 mg, 359 µmol, 0.95 equivalent) , HCl) and 4-(1-chloro-4-methylpyrido[3,4-d]

-7-base)

Add potassium fluoride (87.8 mg, 1.51 mmol, 35.4 µL, 4.00 equivalents) to a solution of morpholine (100 mg, 378 µmol, 1.00 equivalent) in dimethyl sulfoxide (3.00 mL), and stir the solution at 130°C 12 hours. The reaction mixture was diluted with water (15.0 mL), extracted with ethyl acetate (10.0 mL×3), washed with brine (5.00 mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue Things. The residue was purified by preparative TLC (dichloromethane/methanol=10/1) to obtain ( R ) -N -(1-(3-(benzyloxy)-5-(tris) as a yellow solid (Fluoromethyl)phenyl)ethyl)-4-methyl-7-

Hydroxypyrido[3,4- d ]

-1-amine (65.0 mg, 121 µmol, 32.1% yield, 97.8% purity). LCMS [M+1] ⁺ : 524.3.

啉基吡啶并[3,4-d ]嗒

-1-胺（65.0 mg, 124 µmol，1.00當量）、Pd/C（20.0 mg，10%純度）及氫氧化鈀（20.0 mg）於甲醇（5.00 mL）中之溶液在25℃在氫氣氛圍下（15 Psi）在20℃下保持30分鐘。將溶液過濾且在減壓下濃縮，得到殘餘物。將殘餘物藉由製備型HPLC[（Phenomenex luna C18 150×25 mm×10 um；移動相：A相：水（0.225%甲酸），B相：MeCN；B%：12%-42%）]純化，得到呈黃色固體狀之(R )-3-(1-((4-甲基-7-

啉基吡啶并[3,4-d ]嗒

-1-基)胺基)乙基)-5-(三氟甲基)苯酚（12.2 mg，25.2 µmol，20.3%產率，99.4%純度，甲酸鹽）。LCMS [M+1]⁺ : 434.2。Add ( R ) -N -(1-(3-(benzyloxy)-5-(trifluoromethyl)phenyl)ethyl)-4-methyl-7-

Hydroxypyrido[3,4- d ]

A solution of -1-amine (65.0 mg, 124 µmol, 1.00 equivalent), Pd/C (20.0 mg, 10% purity) and palladium hydroxide (20.0 mg) in methanol (5.00 mL) at 25°C under hydrogen atmosphere (15 Psi) Keep at 20°C for 30 minutes. The solution was filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by preparative HPLC [(Phenomenex luna C18 150×25 mm×10 um; mobile phase: phase A: water (0.225% formic acid), phase B: MeCN; B%: 12%-42%)] , To obtain ( R )-3-(1-((4-methyl-7-

Hydroxypyrido[3,4- d ]

-1-yl)amino)ethyl)-5-(trifluoromethyl)phenol (12.2 mg, 25.2 µmol, 20.3% yield, 99.4% purity, formate). LCMS [M+1] ⁺ : 434.2.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.06-9.94 (m, 1H), 9.02 (s, 1H), 8.13 (s, 1H), 7.46 (d, J = 0.8 Hz, 1H), 7.40 (s, 1H), 7.16 (s, 1H), 7.06 (s, 1H), 6.85 (s, 1H), 5.39 (m, 1H), 3.78-3.77 (m, 4H), 3.70-3.69 (m, 4H ), 2.58 (s, 3H), 1.56 (d, J = 6.8 Hz, 3H).

SFC conditions: "Column: Chiralcel OD-3 50×4.6 mm inner diameter, 3 um; mobile phase: phase A is CO ₂ and phase B is methanol (0.05% DEA); gradient dissolution: methanol (0.05% DEA) In 5% to 40% CO ₂ , flow rate: 3 ml/min; detector: PDA; column temperature: 35°C; back pressure: 100 Bar". Example 21-2

（279 mg，1.09 mmol，1.20當量）及(R )-1-(3-(苯甲氧基)-5-(三氟甲基)苯基)乙-1-胺（300 mg，0.90 mmol，1.00當量，HCl）於二甲基亞碸（5.00 mL）中之溶液中添加氟化鉀（263 mg，4.52 mmol，106 µL，5.00當量），且將混合物在130℃下攪拌12小時。將混合物用用水（20.0 mL）稀釋，且用乙酸乙酯（20.0 mL×3）萃取。將合併之有機層用鹽水（20.0 mL×2）洗滌，經硫酸鈉乾燥，過濾，且在減壓下濃縮，得到殘餘物。將殘餘物藉由製備型TLC（矽膠板，石油醚:乙酸乙酯＝1:1，Rf＝0.2）純化，得到呈黃色固體狀之(R )-N -(1-(3-(苯甲氧基)-5-(三氟甲基)苯基)乙基)-7-溴-4-甲基呔

-1-胺（300 mg，581 µmol，64.3%產率）。LCMS [M+1]⁺ : 516.0。Step A: Add 6-bromo-4-chloro-1-methyl

(279 mg, 1.09 mmol, 1.20 equivalents) and ( R )-1-(3-(benzyloxy)-5-(trifluoromethyl)phenyl)ethan-1-amine (300 mg, 0.90 mmol, Potassium fluoride (263 mg, 4.52 mmol, 106 µL, 5.00 equivalents) was added to a solution of 1.00 equivalent, HCl) in dimethyl sulfoxide (5.00 mL), and the mixture was stirred at 130°C for 12 hours. The mixture was diluted with water (20.0 mL), and extracted with ethyl acetate (20.0 mL×3). The combined organic layer was washed with brine (20.0 mL×2), dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by preparative TLC (silica gel plate, petroleum ether: ethyl acetate = 1:1, Rf = 0.2) to obtain ( R ) -N -(1-(3-(benzyl) as a yellow solid (Oxy)-5-(trifluoromethyl)phenyl)ethyl)-7-bromo-4-methyl

-1-amine (300 mg, 581 µmol, 64.3% yield). LCMS [M+1] ⁺ : 516.0.

-1-胺（150 mg，0.29 mmol，1.00當量）、

啉（50.6 mg，0.58 mmol，51.1 µL，2.00當量）、RuPhos（13.6 mg，0.03 mmol，0.10當量）及碳酸銫（284 mg，872 µmol，3.00當量）於二

烷（10.0 mL）中之溶液中添加Pd₂ (dba)₃ （26.6 mg，0.03 mmol，0.10當量），隨後將反應在氮氣氛圍下在100℃下攪拌12小時。用水（15.0 mL）淬滅反應，且將混合物用乙酸乙酯（15.0 mL×3）萃取。將合併之有機層用鹽水（15.0 mL×2）洗滌，經硫酸鈉乾燥，過濾，且在減壓下濃縮，得到殘餘物。將殘餘物藉由製備型TLC（矽膠板，二氯甲烷:甲醇＝10:1，Rf＝0.3）純化，得到呈黃色油狀之(R )-N -(1-(3-(苯甲氧基)-5-(三氟甲基)苯基)乙基)-4-甲基-7-

啉基呔

-1-胺（120 mg，230 µmol，79.1%產率）。LCMS [M+1]⁺ : 523.3。Step B: To ( R ) -N -(1-(3-(benzyloxy)-5-(trifluoromethyl)phenyl)ethyl)-7-bromo-4-methyl

-1-amine (150 mg, 0.29 mmol, 1.00 equivalent),

Phosphine (50.6 mg, 0.58 mmol, 51.1 µL, 2.00 equivalents), RuPhos (13.6 mg, 0.03 mmol, 0.10 equivalents) and cesium carbonate (284 mg, 872 µmol, 3.00 equivalents) in two

_{Pd 2} (dba) ₃ (26.6 mg, 0.03 mmol, 0.10 equivalent) was added to the solution in alkane (10.0 mL), and then the reaction was stirred at 100°C for 12 hours under a nitrogen atmosphere. The reaction was quenched with water (15.0 mL), and the mixture was extracted with ethyl acetate (15.0 mL×3). The combined organic layer was washed with brine (15.0 mL×2), dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by preparative TLC (silica gel plate, dichloromethane: methanol = 10:1, Rf = 0.3) to obtain ( R ) -N -(1-(3-(benzyloxy) as a yellow oil Yl)-5-(trifluoromethyl)phenyl)ethyl)-4-methyl-7-

Linyl

-1-amine (120 mg, 230 µmol, 79.1% yield). LCMS [M+1] ⁺ : 523.3.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 7.98 (d, J = 9.2 Hz, 1H), 7.83 (d, J = 8.8 Hz, 1H), 7.70 (dd, J = 2.8, 9.2 Hz, 1H ), 7.61-7.57 (m, 2H), 7.35-7.29 (m, 5H), 7.17-7.13 (m, 2H), 5.50 (t, J = 6.8 Hz, 1H), 5.14 (s, 2H), 3.85 ( m, 4H), 3.44-3.39 (m, 4H), 2.55 (s, 3H), 1.59 (d, J = 6.8 Hz, 3H).

啉基呔

-1-胺（120 mg，0.03 mmol，1.00當量）於甲醇（10.0 mL）中之溶液中添加Pd/C（80.0 mg，0.03 mmol，10%純度，1.00當量）及氫氧化鈀（80.0 mg，0.03 mmol，1.00當量），隨後將反應在氫氣氛圍（15 psi）下在40℃下攪拌1小時。將反應過濾且在減壓下濃縮，得到殘餘物。將殘餘物藉由製備型HPLC[（管柱：Waters Xbridge 150×25 mm 10 um；移動相：A相：水（10mM NH₄ HCO₃ ），B相：MeCN；B%：28%-58%）]純化，得到呈黃色固體狀之(R )-3-(1-((4-甲基-7-

啉基呔

-1-基)胺基)乙基)-5-(三氟甲基)苯酚（34.0 mg，78.6 µmol，34.2%產率）。LCMS [M+1]⁺ : 433.3。Step C: To ( R ) -N -(1-(3-(benzyloxy)-5-(trifluoromethyl)phenyl)ethyl)-4-methyl-7-

Linyl

-1-amine (120 mg, 0.03 mmol, 1.00 equivalent) in methanol (10.0 mL) was added Pd/C (80.0 mg, 0.03 mmol, 10% purity, 1.00 equivalent) and palladium hydroxide (80.0 mg, 0.03 mmol, 1.00 equivalent), and then the reaction was stirred at 40°C for 1 hour under a hydrogen atmosphere (15 psi). The reaction was filtered and concentrated under reduced pressure to give a residue. The residue was subjected to preparative HPLC [(column: Waters Xbridge 150×25 mm 10 um; mobile phase: phase A: water (10mM NH ₄ HCO ₃ ), phase B: MeCN; B%: 28%-58% )] was purified to obtain ( R )-3-(1-((4-methyl-7-

Linyl

-1-yl)amino)ethyl)-5-(trifluoromethyl)phenol (34.0 mg, 78.6 µmol, 34.2% yield). LCMS [M+1] ⁺ : 433.3.

¹ H NMR (400 MHz, DMSO- d ₆ ): δ = 9.95 (s, 1H), 7.78-7.76 (m, 1H), 7.60-7.58 (m, 2H), 7.29 (d, J = 7.2 Hz, 1H ), 7.18 (s, 1H), 7.09 (s, 1H), 6.84 (s, 1H), 5.48-5.41 (m, 1H), 3.84-3.82 (m, 4H), 3.43-3.40 (m, 4H), 2.55 (s, 3H), 1.57 (d, J = 7.2 Hz, 3H).

啉基吡啶并[3,4-d ]嗒

-1-基)胺基)乙基)苯甲腈

SFC conditions: Chiralcel OD-3 50×4.6 mm inner diameter, 3 um; mobile phase: phase A is CO ₂ and phase B is MeOH (0.05% DEA); gradient dissociation: MeOH (0.05% DEA) at 5% to In 40% CO ₂ ; flow rate: 3 ml/min; detector: PDA; column temperature: 35°C; back pressure: 100 Bar. Example 21-3 ( R )-3-methyl-5-(1-((4-methyl-7-

Hydroxypyrido[3,4- d ]

-1-yl)amino)ethyl)benzonitrile

Step A: Combine 3-acetyl-5-methylbenzonitrile (0.50 g, 3.14 mmol, 1.00 equivalent), (R)-2-methylpropane-2-sulfinamide (495 mg, 4.08 mmol , 1.30 equivalents) and a mixture of titanium ethoxide (1.43 g, 6.28 mmol, 1.30 mL, 2.00 equivalents) in tetrahydrofuran (5.00 mL) was degassed and flushed with nitrogen 3 times, and then the mixture was placed under a nitrogen atmosphere at 70°C Stir for 12 hours. The reaction mixture was then quenched by adding water (10.0 mL) at 25°C, and extracted with ethyl acetate (20.0 mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue Things. The residue was purified (SiO _2, petroleum ether / ethyl acetate = 10 / 1-1 / 1) was purified by column chromatography to give a yellow oil of (R, E) - N - (1- (3 -Cyano-5-methylphenyl)ethylene)-2-methylpropane-2-sulfinamide (730 mg, 2.78 mmol, 88.6% yield). LCMS [M+1] ⁺ : 263.0.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 8.10 (s, 1H), 8.01 (s, 1H), 7.86 (d, J = 0.4 Hz, 1H), 2.73 (s, 3H), 2.42 (s , 3H), 1.23 (s, 9H).

Step B: To ( R , E ) -N -(1-(3-cyano-5-methylphenyl)ethylene)-2-methylpropane-2-sulfinamide at 0°C (0.30 g, 1.14 mmol, 1.00 equivalent) To a solution in tetrahydrofuran (3.00 mL) was added sodium borohydride (130 mg, 3.43 mmol, 3.00 equivalent). The mixture was stirred at 20°C for 2 hours. The mixture was quenched with ammonium chloride solution (10.0 mL) and concentrated under reduced pressure to give a residue. The residue was diluted with ethyl acetate (60.0 ml), and the organic layer was washed with brine (20.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO ₂ , petroleum ether/ethyl acetate = 1/1) to obtain ( R ) -N -(1-(3-cyano-5-methyl) as a yellow oil (Phenyl)ethyl)-2-methylpropane-2-sulfinamide (280 mg, 1.06 mmol, 92.6% yield). LCMS [M+1] ⁺ : 265.1.

¹ H NMR (400 MHz, DMSO- d 6) δ = 7.67 (s, 1H), 7.56-7.52 (m, 2H), 5.76 (d, J = 7.6 Hz, 1H), 4.45-4.35 (m, 1H) , 2.35 (s, 3H), 1.38 (d, J = 7.2 Hz, 3H), 1.12 (s, 9H).

Step C: Add ( R ) -N -(1-(3-cyano-5-methylphenyl)ethyl)-2-methylpropane-2-sulfinamide (250 mg, 946 µmol, 1.00 Equivalent) a mixture of hydrochloric acid/ethyl acetate (4.0 M, 2.60 mL, 11.0 equivalent) was stirred at 25°C for 1 hour. The reaction mixture was quenched with saturated sodium bicarbonate solution (5.00 mL), and extracted with ethyl acetate (10.0 mL×3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain 3 as a yellow oil -(1-Aminoethyl)-5-methylbenzonitrile (130 mg, 811 µmol, 85.8% yield).

¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 7.62 (s, 1H), 7.53 (s, 1H), 7.48 (d, J = 0.4 Hz, 1H), 4.01 (q, J = 6.8 Hz, 1H ), 2.34 (s, 3H), 1.24 (d, J = 6.8 Hz, 3H).

-7-基)

啉（165 mg，624 µmol，1.00當量）及氟化鉀（109 mg，1.87 mmol，3.00當量）於二甲基亞碸（0.20 mL）中之混合物脫氣且用氮氣沖洗3次，且隨後將混合物在氮氣氛圍下在130℃下攪拌12小時。在25℃下將反應混合物用水（10.0 mL）淬滅，且用乙酸乙酯（10.0 mL×3）萃取，經無水硫酸鈉乾燥，過濾，且在減壓下濃縮，得到殘餘物。將殘餘物藉由製備型HPLC[管柱：Waters Xbridge 150×25 mm 10um；移動相：A相：水（10 mM NH₄ HCO₃ ），B相：MeCN；B%：24%-54%]純化，得到呈黃色固體狀之3-甲基-5-(1-((4-甲基-7-

啉基吡啶并[3,4-d]嗒

-1-基)胺基)乙基)苯甲腈（80.0 mg，206 µmol，32.9%產率，99.9%純度）。用SFC[管柱：DAICEL CHIRALPAK AD（250 mm×30 mm，10 um）；移動相：A相：0.1% NH₄ OH/MeOH，B相：CO₂ ；B%：25%]分離鏡像異構體。Step D: Combine 3-(1-aminoethyl)-5-methylbenzonitrile (100 mg, 624 µmol, 1.00 equivalent), 4-(1-chloro-4-methylpyrido[3,4 -d] Da

-7-base)

A mixture of morpholine (165 mg, 624 µmol, 1.00 equivalent) and potassium fluoride (109 mg, 1.87 mmol, 3.00 equivalent) in dimethyl sulfoxide (0.20 mL) was degassed and flushed with nitrogen 3 times, and then The mixture was stirred at 130°C for 12 hours under a nitrogen atmosphere. The reaction mixture was quenched with water (10.0 mL) at 25°C, and extracted with ethyl acetate (10.0 mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was subjected to preparative HPLC [column: Waters Xbridge 150×25 mm 10um; mobile phase: phase A: water (10 mM NH ₄ HCO ₃ ), phase B: MeCN; B%: 24%-54%] Purification to obtain 3-methyl-5-(1-((4-methyl-7-

Hydroxypyrido[3,4-d]

-1-yl)amino)ethyl)benzonitrile (80.0 mg, 206 µmol, 32.9% yield, 99.9% purity). Use SFC[Column: DAICEL CHIRALPAK AD (250 mm×30 mm, 10 um); mobile phase: A phase: 0.1% NH ₄ OH/MeOH, B phase: CO ₂ ; B%: 25%] to separate mirror isomers body.

啉基吡啶并[3,4-d ]嗒

-1-基)胺基)乙基)苯甲腈（第一溶離異構體）： Example 21-3 , ( R )-3-methyl-5-(1-((4-methyl-7-

Hydroxypyrido[3,4- d ]

-1-yl)amino)ethyl)benzonitrile (first lysomer):

¹ H NMR (400 MHz, CD ₃ OD) δ = 8.97 (s, 1H), 7.56 (s, 2H), 7.34 (s, 1H), 7.27 (s, 1H), 5.37 (q, J = 6.8 Hz, 1H), 3.85-3.80 (m, 4H), 3.76-3.72 (m, 4H), 2.62 (s, 3H), 2.33 (s, 3H), 1.63 (d, J = 6.8 Hz, 3H)

LCMS [M+1] ⁺ : 389.2.

啉基呔

-1-基)胺基)乙基)苯甲腈

SFC conditions: "Column: Chiralpak AD-3 50 × 4.6 mm inner diameter, 3 um; mobile phase: A phase is CO _2, and phase B was methanol (0.05% DEA); eluting gradient: MeOH (0.05% DEA) In 5% to 40% CO ₂ ; Flow rate: 3 ml/min; Detector: PDA; Column temperature: 35°C; Back pressure: 100 Bar" Example 21-4 ( R )-3-methyl-5- (1-((4-methyl-7-

Linyl

-1-yl)amino)ethyl)benzonitrile

（161 mg，624 µmol，1.00當量）及氟化銫（284 mg，1.87 mmol，69.0 µL，3.00當量）於二甲基亞碸（0.20 mL）中之混合物脫氣且用氮氣沖洗3次，且隨後將混合物在氮氣氛圍下在130℃下攪拌1小時。將反應混合物在25℃下藉由添加水（10.0 mL）來淬滅，用乙酸乙酯（10.0 mL×3）萃取，經無水硫酸鈉乾燥，過濾，且在減壓下濃縮，得到殘餘物。將殘餘物藉由製備型TLC（SiO_{2 ，} 石油醚/乙酸乙酯＝1:1）純化，得到呈黃色油狀之3-(1-((7-溴-4-甲基呔

-1-基)胺基)乙基)-5-甲基苯甲腈（50.0 mg，131 µmol，21.0%產率）。LCMS [M+1]⁺ : 382.9。Step A: Combine 3-(1-aminoethyl)-5-methylbenzonitrile (100mg, 624 µmol, 1.00 equivalent), 6-bromo-4-chloro-1-methyl

The mixture of (161 mg, 624 µmol, 1.00 equivalent) and cesium fluoride (284 mg, 1.87 mmol, 69.0 µL, 3.00 equivalent) in dimethyl sulfoxide (0.20 mL) is degassed and flushed with nitrogen 3 times, and The mixture was then stirred at 130°C for 1 hour under a nitrogen atmosphere. The reaction mixture was quenched by adding water (10.0 mL) at 25°C, extracted with ethyl acetate (10.0 mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by preparative TLC (SiO _{2 ,} petroleum ether/ethyl acetate=1:1) to obtain 3-(1-((7-bromo-4-methyl) as a yellow oil

-1-yl)amino)ethyl)-5-methylbenzonitrile (50.0 mg, 131 µmol, 21.0% yield). LCMS [M+1] ⁺ : 382.9.

-1-基)胺基)乙基)-5-甲基苯甲腈（40.0 mg，105 µmol，1.00當量）、

啉（36.6 mg，420µmol， 36.9 µL，4.00當量）、碳酸銫（103 mg，315 µmol，3.00當量）及RuPhos Pd G₃ （87.8 mg，105 µmol，1.00當量）於二

烷（1.00 mL）中之混合物脫氣且用氮氣沖洗3次，且隨後將混合物在氮氣氛圍下在80℃下攪拌2小時。將反應混合物在25℃下藉由添加水（10.0 mL）來淬滅，用乙酸乙酯（10.0 mL×3）萃取，經無水硫酸鈉乾燥，過濾，且在減壓下濃縮，得到殘餘物。將殘餘物藉由製備型HPLC[管柱：Waters Xbridge 150×25 mm 10 um；移動相：A相：水（10 mM NH₄ HCO₃ ，B相：MeCN；B%：25%-55%]純化，得到呈白色固體狀之3-甲基-5-(1-((4-甲基-7-

啉基呔

-1-基)胺基)乙基)苯甲腈（20.0 mg，51.5 µmol，49.0%產率，99.7%純度）。使用SFC（管柱：DAICEL CHIRALPAK AD（250 mm×30 mm，10 um）；移動相：A相：NH₄ OH/MeOH，B相：CO₂ ；B%：30%]）純化，得到呈黃色固體狀之(R )-3-甲基-5-(1-((4-甲基-7-

啉基呔

-1-基)胺基)乙基)苯甲腈（4.51 mg）。LCMS [M+1]⁺ : 388.2.Add 3-(1-((7-bromo-4-methyl

-1-yl)amino)ethyl)-5-methylbenzonitrile (40.0 mg, 105 µmol, 1.00 equivalent),

Phyrin (36.6 mg, 420 µmol, 36.9 µL, 4.00 equivalent), cesium carbonate (103 mg, 315 µmol, 3.00 equivalent) and RuPhos Pd G ₃ (87.8 mg, 105 µmol, 1.00 equivalent) in two

The mixture in alkane (1.00 mL) was degassed and flushed with nitrogen 3 times, and then the mixture was stirred at 80°C for 2 hours under a nitrogen atmosphere. The reaction mixture was quenched by adding water (10.0 mL) at 25°C, extracted with ethyl acetate (10.0 mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was subjected to preparative HPLC [column: Waters Xbridge 150×25 mm 10 um; mobile phase: phase A: water (10 mM NH ₄ HCO ₃ , phase B: MeCN; B%: 25%-55%) Purification to obtain 3-methyl-5-(1-((4-methyl-7-

Linyl

-1-yl)amino)ethyl)benzonitrile (20.0 mg, 51.5 µmol, 49.0% yield, 99.7% purity). Purified by SFC (column: DAICEL CHIRALPAK AD (250 mm×30 mm, 10 um); mobile phase: A phase: NH ₄ OH/MeOH, B phase: CO ₂ ; B%: 30%]) to obtain a yellowish color ( R )-3-methyl-5-(1-((4-methyl-7-

Linyl

-1-yl)amino)ethyl)benzonitrile (4.51 mg). LCMS [M+1] ⁺ : 388.2.

¹ H NMR (400 MHz, CD ₃ OD) δ = 7.88 (d, J = 9.2 Hz, 1H), 7.59-7.52 (m, 4H), 7.32 (s, 1H), 5.41 (q, J = 6.8 Hz, 1H), 3.91-3.84 (m, 4H), 3.46-3.40 (m, 4H), 2.61 (s, 3H), 2.32 (s, 3H), 1.64 (d, J = 7.2 Hz, 3H).

-1-胺 7-((S )-4-(二甲基胺基)-3,3-二氟哌啶-1-基)-4-甲基-N -((R )-1-(2-甲基-3-(三氟甲基)苯基)乙基)呔

-1-胺

SFC conditions: column: Chiralpak AD-3 50×4.6 mm inner diameter, 3 um; mobile phase: phase A is CO ₂ , phase B is MeOH (0.05% DEA); gradient dissolution: MeOH (0.05% DEA) in 5 % To 40% CO ₂ ; flow rate: 3 ml/min; detector: PDA; column temperature: 35°C; back pressure: 100 Bar. Example 21-5 and Example 21-6 7-(( R )-4-(dimethylamino)-3,3-difluoropiperidin-1-yl)-4-methyl- N -(( R )-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)

-1-amine 7-(( S )-4-(dimethylamino)-3,3-difluoropiperidin-1-yl)-4-methyl- N -(( R )-1-( 2-methyl-3-(trifluoromethyl)phenyl)ethyl)

-1-amine

Step A: Add paraformaldehyde to a solution of 4-amino-3,3-difluoropiperidine-1-carboxylic acid tert-butyl ester (300 mg, 1.27 mmol, 1.00 equivalent) in methanol (10.0 mL) (1.00 g, 1.27 mmol, 1.00 equivalent) and acetic acid (7.63 mg, 127 µmol, 7.26 μL, 0.10 equivalent), the reaction was stirred at 50°C for 30 minutes, and then sodium cyanoborohydride (479 mg , 7.62 mmol, 6.00 equivalent). The reaction mixture was stirred at 50°C for 16 hours, and then concentrated under reduced pressure to obtain a residue. The residue was diluted with water (50.0 mL), and extracted with ethyl acetate (30.0 mL×3). The combined organic layer was washed with brine (50.0 mL×3), dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 5/1 to 3/1) to obtain compound 4-(dimethylamino)-3 as a white solid, Tertiary butyl 3-difluoropiperidine-1-carboxylate (320 mg, 1.21 mmol, 95.4% yield). LCMS [M+1] ⁺ : 265.1.

烷溶液（4.00 M，5.33 mL，17.6當量）。將反應混合物在0℃下攪拌30分鐘，隨後在減壓下濃縮，得到呈白色固體狀之化合物3,3-二氟-N ,N -二甲基哌啶-4-胺（190 mg，1.16 mmol，95.6%產率），其直接用於下一步。Step B: To a solution of 4-(dimethylamino)-3,3-difluoropiperidine-1-carboxylic acid tert-butyl ester (320 mg, 1.21 mmol, 1.00 equivalent) in acetonitrile (1.00 mL) Add HCl/two

Alkane solution (4.00 M, 5.33 mL, 17.6 equivalents). The reaction mixture was stirred at 0°C for 30 minutes, and then concentrated under reduced pressure to obtain the compound 3,3-difluoro- N , N -dimethylpiperidin-4-amine (190 mg, 1.16) as a white solid mmol, 95.6% yield), which was used directly in the next step.

-1-胺（220 mg，519 μmol，1.00當量）、3,3-3,3-二氟-N ,N -二甲基哌啶-4-胺（128 mg，778 μmol，1.50當量）、第三丁醇鈉（199 mg，2.07 mmol，4.00當量）及RuPhos Pd G₃ （43.4 mg，51.9 μmol，0.10當量）於二

烷（5.00 mL）中之混合物脫氣且用氮氣沖洗3次，且隨後將反應混合物在氮氣氛圍下在110℃下攪拌16小時。將反應混合物冷卻至25℃，用水（30.0 mL）稀釋，且用乙酸乙酯（30.0 mL×3）萃取。將合併之有機層用鹽水（40.0 mL×3）洗滌，經硫酸鈉乾燥，過濾，且在減壓下濃縮，得到殘餘物。將殘餘物首先藉由製備型TLC（二氯甲烷:甲醇＝10:1）純化，得到白色固體。LCMS [M+1] +: 508.3。Step C: Add ( R )-7-bromo-4-methyl- N -(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)

-1-amine (220 mg, 519 μmol, 1.00 equivalent), 3,3-3,3-difluoro- N , N -dimethylpiperidin-4-amine (128 mg, 778 μmol, 1.50 equivalent), Sodium tertiary butoxide (199 mg, 2.07 mmol, 4.00 equivalent) and RuPhos Pd G ₃ (43.4 mg, 51.9 μmol, 0.10 equivalent) in two

The mixture in alkane (5.00 mL) was degassed and flushed with nitrogen 3 times, and then the reaction mixture was stirred at 110° C. for 16 hours under a nitrogen atmosphere. The reaction mixture was cooled to 25°C, diluted with water (30.0 mL), and extracted with ethyl acetate (30.0 mL×3). The combined organic layer was washed with brine (40.0 mL×3), dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was first purified by preparative TLC (dichloromethane: methanol = 10:1) to obtain a white solid. LCMS [M+1] +: 508.3.

-1-胺及7-((S)-4-(二甲基胺基)-3,3-二氟哌啶-1-基)-4-甲基-N-((R)-1-(2-甲基-3-(三氟甲基)苯基)乙基)呔

-1-胺。This compound was further purified using SFC (column: DAICEL CHIRALCEL OD-H (250 mm×30 mm, 5 μm); mobile phase: phase A: 0.1% NH3 in H2O, phase B: MeOH; B%: 20 %) Separate the diastereomers to obtain the separated isomers 7-((R)-4-(dimethylamino)-3,3-difluoropiperidin-1-yl)-4-methyl -N-((R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)

-1-amine and 7-((S)-4-(dimethylamino)-3,3-difluoropiperidin-1-yl)-4-methyl-N-((R)-1- (2-Methyl-3-(trifluoromethyl)phenyl)ethyl)

-1-amine.

Spectral data of Example 21 -5 (first soluble isomer):

LCMS [M+1] ⁺ :508.2

¹ H NMR (400 MHz, CD ₃ OD) δ = 8.24 (d, J = 9.2 Hz, 1H), 8.00 (d, J = 2.0 Hz, 1H), 7.88 (dd, J = 2.4, 9.2 Hz, 1H) , 7.78-7.72 (m, 1H), 7.55 (br d, J = 7.6 Hz, 1H), 7.34-7.25 (m, 1H), 5.62-5.51 (m, 1H), 5.01-4.95 (m, 1H), 4.77-4.64 (m, 1H), 4.38-4.20 (m, 1H), 3.78-3.63 (m, 1H), 3.44 (br t, J = 12.0 Hz, 1H), 3.10 (s, 6H), 2.80 (s , 3H), 2.65 (s, 3H), 2.62-2.53 (m, 1H), 2.27-2.13 (m, 1H), 1.71 (d, J = 6.8 Hz, 3H).

Example 21-6 (Second soluble isomer) spectral data:

LCMS [M+1] ⁺ :508.2

¹ H NMR (400 MHz, CD ₃ OD) δ = 8.24 (d, J = 9.2 Hz, 1H), 8.01 (d, J = 2.0 Hz, 1H), 7.87 (dd, J = 2.4, 9.2 Hz, 1H) , 7.77 (d, J = 7.6 Hz, 1H), 7.55 (d, J = 8.0 Hz, 1H), 7.35-7.24 (m, 1H), 5.62-5.52 (m, 1H), 5.01-4.95 (m, 1H) ), 4.76-4.66 (m, 1H), 4.38-4.20 (m, 1H), 3.81-3.62 (m, 1H), 3.44 (br t, J = 12.4 Hz, 1H), 3.15 (s, 6H), 2.80 (s, 3H), 2.65 (s, 3H), 2.61-2.52 (m, 1H), 2.28-2.13 (m, 1H), 1.72 (d, J = 6.8 Hz, 3H). Example 21-7

Step A: Combine 1-(3-iodophenyl)ethan-1-one (4.60 g, 18.7 mmol, 1.00 equivalent), ethyl 2-bromo-2,2-difluoroacetate (4.17 g, 20.6 mmol, 2.64 mL, 1.10 equivalents) and a mixture of copper powder (3.56 g, 56.1 mmol, 398 µL, 3.00 equivalents) in DMSO (50.0 mL) was degassed and flushed with nitrogen 3 times, and the mixture was placed under a nitrogen atmosphere at 60°C Stir for 12 hours. The mixture was diluted with ethyl acetate (100 mL). It was filtered, and the filtrate was washed with brine (50.0 mL×3), dried, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 80/1 to 30/1) to obtain 2-(3-acetylphenyl)-2 as a colorless oil ,2-Difluoroethyl acetate (3.80 g, 15.7 mmol, 83.9% yield).

¹ H NMR (400 MHz, CDCl ₃ ) δ = 8.20 (s, 1H), 8.10 (d, J = 7.6 Hz, 1H), 7.84-7.80 (m, 1H), 7.59 (t, J = 7.2 Hz, 1H ), 4.37-4.29 (m, 2H), 2.65 (s, 3H), 1.32 (t, J = 7.2 Hz, 3H).

Step B: Add 2-(3-acetylphenyl)-2,2-difluoroacetate (2.00 g, 8.26 mmol, 1.00 equivalent) and ( R )-2-methylpropane-2-sulfinate To a solution of amide (1.30 g, 10.8 mmol, 1.30 equivalents) in THF (40.0 mL) was added titanium(IV) butoxide (3.77 g, 16.5 mmol, 3.42 mL, 2.00 equivalents) and 1,2-dimethoxy Ethane (744 mg, 8.26 mmol, 858 µL, 1.00 equivalent), and the mixture was stirred at 70°C for 12 hours. The reaction mixture was diluted with ethyl acetate (100 mL) and water (5.00 mL), filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 10/1 to 5/1) to obtain ( R )-2-(3-(1-() as a yellow oil (Tertiary butylsulfinyl)imino)ethyl)phenyl) ethyl-2,2-difluoroacetate (2.40 g, 6.95 mmol, 84.2% yield).

Step C: At 0 ℃, to ( R )-2-(3-(1-((tertiary butylsulfinyl)imino)ethyl)phenyl)-2,2-difluoroacetic acid To a solution of ethyl ester (2.20 g, 6.37 mmol, 1.00 equivalent) in methanol (20.0 mL) was added sodium borohydride (964 mg, 25.5 mmol, 4.00 equivalent), and the mixture was stirred at 28°C for 1 hour. The mixture was diluted with water (20.0 mL), and extracted with ethyl acetate (50.0 mL×3), and the combined organic phase was dried and concentrated under reduced pressure. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 2/1 to 1/1) to obtain ( R ) -N -(( R )-1- (3-(1,1-Difluoro-2-hydroxyethyl)phenyl)ethyl)-2-methylpropane-2-sulfinamide (0.90 g, 2.95 mmol, 46.3% yield) and present (R ) -N -(( S )-1-(3-(1,1-difluoro-2-hydroxyethyl)phenyl)ethyl)-2-methylpropane-2-yellow oil Sulfonamide (0.90 g, 2.95 mmol, 46.3% yield). LCMS [M+1] ⁺ : 306.1.

Step D: To ( R ) -N -(( R )-1-(3-(1,1-difluoro-2-hydroxyethyl)phenyl)ethyl)-2-methylpropane-2-ylidene Sulfonamide (0.90 g, 2.95 mmol, 1.00 equivalent) was added to a solution of THF (8.00 mL) and water (2.00 mL) with iodine (224 mg, 884 µmol, 178 µL, 0.30 equivalent), and the mixture was heated at 50 Stir at °C for 1 hour. The reaction mixture was then diluted with saturated aqueous sodium sulfite solution (10.0 ml) and sodium bicarbonate aqueous solution (10.0 mL), and the resulting mixture was extracted with dichloromethane/methanol (10:1, 10.0 mL×3). The combined organic phase was dried and concentrated under reduced pressure to obtain ( R )-2-(3-(1-aminoethyl)phenyl)-2,2-difluoroethane-1 as a yellow oil -Alcohol (450 mg, crude).

-7-基)

啉（200 mg，756 µmol，1.00當量）、((R )-2-(3-(1-胺基乙基)苯基)-2,2-二氟乙烷-1-醇（152 mg，756 µmol，1.00當量）、BrettPhos Pd G₃ （68.5 mg，75.6 µmol，0.10當量）及第三丁醇鈉（218 mg，2.27 mmol，3.00當量）於二

烷（3.00 mL）中之混合物脫氣且用氮氣沖洗3次，隨後將混合物在氮氣氛圍下在100℃下攪拌1小時。將反應混合物過濾且在減壓下濃縮。將殘餘物藉由製備型HPLC[管柱：Phenomenex Luna C18 150×25 mm×10 um；移動相：A相：水（0.225%甲酸，B相：乙腈；B%：9%-39%）純化，得到呈黃色固體狀之(R )-2,2-二氟-2-(3-(1-((4-甲基-7-

啉基吡啶并[3,4-d ]嗒

-1-基)胺基)乙基)苯基)乙-1-醇（73.0 mg，170 µmol，22.5%產率，99.9%純度）。LCMS [M+1]⁺ : 430.1。Step E: Add 4-(1-chloro-4-methylpyrido[3,4-d]

-7-base)

Phyloline (200 mg, 756 µmol, 1.00 equivalent), (( R )-2-(3-(1-aminoethyl)phenyl)-2,2-difluoroethane-1-ol (152 mg, 756 µmol, 1.00 equivalent), BrettPhos Pd G ₃ (68.5 mg, 75.6 µmol, 0.10 equivalent) and sodium tert-butoxide (218 mg, 2.27 mmol, 3.00 equivalent) in two

The mixture in alkane (3.00 mL) was degassed and flushed with nitrogen 3 times, then the mixture was stirred at 100°C for 1 hour under a nitrogen atmosphere. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC [column: Phenomenex Luna C18 150×25 mm×10 um; mobile phase: phase A: water (0.225% formic acid, phase B: acetonitrile; B%: 9%-39%) , To obtain ( R )-2,2-difluoro-2-(3-(1-((4-methyl-7-

Hydroxypyrido[3,4- d ]

-1-yl)amino)ethyl)phenyl)ethan-1-ol (73.0 mg, 170 µmol, 22.5% yield, 99.9% purity). LCMS [M+1] ⁺ : 430.1.

¹ H NMR (400 MHz, CD ₃ OD) δ = 9.11 (s, 1H), 8.48 (s, 1H), 7.62 (s, 1H), 7.56 (br d, J = 6.4 Hz, 1H), 7.46-7.35 (m, 3H), 5.44-5.34 (m, 1H), 3.95-3.81 (m, 10H), 2.71 (s, 3H), 1.69 (d, J = 6.8 Hz, 3H). Example 21-8

啉基呔

-1-胺（100 mg，224 µmol，1.00當量）及四氟硼酸（253 mg，1.15 mmol，179 µL，40.0%純度，5.13當量）於水（3.00 mL）中之混合物中，將混合物在0℃下攪拌30分鐘。過濾反應混合物，且將濾餅在減壓下濃縮，得到呈黃色固體狀之(R )-4-甲基-3-(1-((4-甲基-7-

啉基呔

-1-基)胺基)乙基)-5-(三氟甲基)重氮苯四氟硼酸鹽（100 mg，粗製）。LCMS [M-28]⁺ : 429.0。Step A: At 0℃, add a solution of sodium nitrite (20.1 mg, 292 µmol, 1.30 equivalent) in water (0.60 mL) dropwise to ( R )- N -(1-(5-amino- 2-Methyl-3-(trifluoromethyl)phenyl)ethyl)-4-methyl-7-

Linyl

-1-amine (100 mg, 224 µmol, 1.00 equivalent) and tetrafluoroboric acid (253 mg, 1.15 mmol, 179 µL, 40.0% purity, 5.13 equivalent) in a mixture of water (3.00 mL). Stir at °C for 30 minutes. The reaction mixture was filtered, and the filter cake was concentrated under reduced pressure to obtain ( R )-4-methyl-3-(1-((4-methyl-7-

Linyl

-1-yl)amino)ethyl)-5-(trifluoromethyl)benzenediazonium tetrafluoroborate (100 mg, crude). LCMS [M-28] ⁺ : 429.0.

啉基呔

-1-基)胺基)乙基)-5-(三氟甲基)重氮苯四氟硼酸鹽（100 mg，184 µmol，1.00當量）於甲苯（1.00 mL）中之溶液加熱至110℃，將混合物在110℃下攪拌3小時。在減壓下濃縮反應混合物，得到殘餘物。將殘餘物藉由製備型HPLC[管柱：Phenomenex luna C18 80×40 mm×3 um；移動相：A相：水（0.04% HCl），B相：乙腈；B%：28%-52%]純化，得到呈黃色固體狀之(R )-N -(1-(5-氟-2-甲基-3-(三氟甲基)苯基)乙基)-4-甲基-7-

啉基呔

-1-胺（13.1 mg，28.9 µmol，15.8%產率，99.3%純度，鹽酸鹽）。LCMS [M+1]⁺ : 449.1。Step B: Add ( R )-4-methyl-3-(1-((4-methyl-7-

Linyl

-1-yl)amino)ethyl)-5-(trifluoromethyl)benzenediazonium tetrafluoroborate (100 mg, 184 µmol, 1.00 equivalent) in toluene (1.00 mL) is heated to 110°C , The mixture was stirred at 110°C for 3 hours. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was subjected to preparative HPLC [column: Phenomenex luna C18 80×40 mm×3 um; mobile phase: phase A: water (0.04% HCl), phase B: acetonitrile; B%: 28%-52%] Purified to obtain ( R ) -N -(1-(5-fluoro-2-methyl-3-(trifluoromethyl)phenyl)ethyl)-4-methyl-7- as a yellow solid

Linyl

-1-amine (13.1 mg, 28.9 µmol, 15.8% yield, 99.3% purity, hydrochloride). LCMS [M+1] ⁺ : 449.1.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 14.75 (br s, 1H), 8.58-8.41 (m, 1H), 8.22-8.15 (m, 1H), 7.81 (s, 1H), 7.79-7.74 (m, 1H), 7.62-7.56 (m, 1H), 7.48-7.43 (m, 1H), 5.50-5.37 (m, 1H), 3.85-3.80 (m, 4H), 3.72-3.65 (m, 4H) , 2.73 (s, 3H), 2.54 (s, 3H), 1.64-1.58 (m, 3H).

并[1,2-c ][1,3]

-2-基)-4-甲基呔

-1-基)胺基)乙基)-2-甲基苯甲腈

SFC conditions: Chiralcel OD-3 3 µm, 0.46 cm inner diameter×5 cm L; mobile phase: A is SFC CO ₂ , B is MeOH (0.05% isopropylamine); gradient dissolution: B in A from 10 in 3 minutes % Increased to 40%; flow rate: 4.0 ml/min; column temperature: 35°C; back pressure: 100 Bar. Example 21-9 3-(( R )-1-((5-fluoro-7-(( R )-hexahydro-2 H ,6 H -pyridine

And [1,2- c ][1,3]

-2-yl)-4-methyl

-1-yl)amino)ethyl)-2-methylbenzonitrile

Step A: At 0℃, add 2-amino-5-bromo-3-fluorobenzoic acid (2.00 g, 8.55 mmol, 1.00 equivalent) in hydrochloric acid (4.0 M, 21.4 mL, 10.0 equivalent) and water (10.0 mL ) Was added with sodium nitrite (708 mg, 10.3 mmol, 1.20 equivalents), and then the mixture was stirred at the same temperature for 30 minutes. After this time, potassium iodide solution (2.13 g, 12.8 mmol, 1.50 equivalents) was added dropwise, and then the mixture was heated to 90° C. and stirred for 30 minutes. The mixture was cooled, and the pH was adjusted to pH=9 with potassium carbonate, and then filtered. The filtrate was adjusted to pH=4 with HCl (4.0 M in water), filtered, and the precipitate was dried under vacuum to obtain 5-bromo-3-fluoro-2-iodobenzoic acid (2.40 g, 6.96 mmol, 81.4% yield).

¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 14.06-13.55 (m, 1H), 7.79-7.72 (m, 1H), 7.69-7.64 (m, 1H).

Step B: At 0℃, add dropwise to a solution of 5-bromo-3-fluoro-2-iodobenzoic acid (2.40 g, 6.96 mmol, 1.00 equivalent) in toluene (24.0 mL) and methanol (8.00 mL) Trimethylsilyl diazomethane (2.0 M, 6.96 mL, 2.00 equivalents) was added, and the mixture was stirred at 20°C for 30 minutes. The reaction mixture was then concentrated under reduced pressure, and the residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=1/0 to 10/1) to obtain 5- Methyl bromo-3-fluoro-2-iodobenzoate (2.47 g, 6.88 mmol, 98.9% yield).

¹ H NMR (400 MHz, CDCl ₃ ) δ = 7.76-7.69 (m, 1H), 7.40-7.33 (m, 1H), 3.96 (s, 3H).

烷（30.0 mL）中之混合物脫氣且用氮氣沖洗（3次），且隨後將混合物在氮氣氛圍下在80℃下攪拌12小時。隨後將混合物倒入氟化鉀飽和溶液（於水中，50.0 mL）中，且攪拌30分鐘。用乙酸乙酯（100 mL×3）萃取水相，且用鹽水（50.0 mL×3）洗滌合併之有機相，經無水硫酸鈉乾燥，過濾，且在減壓下濃縮。將殘餘物藉由管柱層析法（SiO₂ ，石油醚/乙酸乙酯＝100/1至20/1）純化，得到呈黃色油狀之5-溴-2-(1-乙氧基乙烯基)-3-氟苯甲酸甲酯（1.80 g，5.94 mmol，86.3%產率）。Step C: Combine 5-bromo-3-fluoro-2-iodobenzoic acid methyl ester (2.47 g, 6.88 mmol, 1.00 equivalent), tributyl(1-ethoxyvinyl)tin (2.73 g, 7.57 mmol, 2.55 mL, 1.10 equivalent) and Pd(PPh ₃ ) ₂ Cl ₂ (483 mg, 688 µmol, 0.10 equivalent) in two

The mixture in alkane (30.0 mL) was degassed and flushed with nitrogen (3 times), and then the mixture was stirred at 80°C for 12 hours under a nitrogen atmosphere. The mixture was then poured into a saturated solution of potassium fluoride (in water, 50.0 mL) and stirred for 30 minutes. The aqueous phase was extracted with ethyl acetate (100 mL×3), and the combined organic phase was washed with brine (50.0 mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 100/1 to 20/1) to obtain 5-bromo-2-(1-ethoxyethylene) as a yellow oil Methyl)-3-fluorobenzoate (1.80 g, 5.94 mmol, 86.3% yield).

¹ H NMR (400 MHz, CDCl ₃ ) δ = 7.69-7.65 (m, 1H), 7.44-7.37 (m, 1H), 4.50 (d, J = 2.4 Hz, 1H), 4.38-4.34 (m, 1H) , 3.90-3.85 (m, 5H), 1.32 (t, J = 6.8 Hz, 3H).

Step D: Add hydrochloric acid to a solution of methyl 5-bromo-2-(1-ethoxyvinyl)-3-fluorobenzoate (1.80 g, 5.94 mmol, 1.00 equivalent) in THF (20.0 mL) (2.0 M, 8.91 mL, 3.00 equivalents), and the mixture was stirred at 20°C for 1 hour. Then the pH of the mixture was adjusted to pH=7 with saturated aqueous sodium bicarbonate solution, and the solution was extracted with ethyl acetate (30.0 mL×2). The combined organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 50/1 to 30/1) to obtain 2-acetyl-5-bromo-3-fluoro as a yellow oil Methyl benzoate (1.40 g, 5.09 mmol, 85.7% yield).

¹ H NMR (400 MHz, CDCl ₃ ) δ = 7.91 (s, 1H), 7.54-7.41 (m, 1H), 3.91 (s, 3H), 2.59 (s, 3H).

-1-醇（580 mg，2.26 mmol，51.7%產率）。Step E: Add hydrazine hydrate (334 mg, 6.54 mmol) to a solution of methyl 2-acetyl-5-bromo-3-fluorobenzoate (1.20 g, 4.36 mmol, 1.00 equivalent) in ethanol (10.0 mL) , 325 µL, 98% purity, 1.50 equivalents), and the mixture was stirred at 60°C for 1 hour. The mixture was then cooled to 20°C, filtered, and the precipitate was dried under vacuum to obtain 7-bromo-5-fluoro-4-methyl as a white solid

-1-ol (580 mg, 2.26 mmol, 51.7% yield).

¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 12.7 (br s, 1H), 8.17 (d, J = 1.6 Hz, 1H), 8.15-8.08 (m, 1H), 2.56 (d, J = 6.8 Hz, 3H).

-1-醇（300 mg，1.17 mmol，1.00當量）於三氯氧磷（6.00 mL）中之溶液中添加N,N- 二異丙基乙胺（453 mg，3.50 mmol，10.0 µL，3.00當量），且將混合物在110℃下攪拌2小時。隨後將混合物用碳酸氫鈉水溶液淬滅，且用乙酸乙酯（10.0 mL×3）萃取。將合併之有機相經無水硫酸鈉乾燥，在減壓下濃縮，且將殘餘物藉由管柱層析法（SiO₂ ，石油醚/乙酸乙酯＝5/1）純化，得到呈橙色固體狀之7-溴-1-氯-5-氟-4-甲基呔

（150 mg，544 µmol，46.7%產率）。LCMS [M+1]⁺ : 276.8。Step F: To 7-bromo-5-fluoro-4-methyl

-1-ol (300 mg, 1.17 mmol, 1.00 equivalent) in phosphorus oxychloride (6.00 mL) was added N,N -diisopropylethylamine (453 mg, 3.50 mmol, 10.0 µL, 3.00 equivalent) ), and the mixture was stirred at 110°C for 2 hours. Then the mixture was quenched with aqueous sodium bicarbonate solution, and extracted with ethyl acetate (10.0 mL×3). The combined organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 5/1) to obtain an orange solid Of 7-bromo-1-chloro-5-fluoro-4-methyl

(150 mg, 544 µmol, 46.7% yield). LCMS [M+1] ⁺ : 276.8.

（150 mg，544 µmol，1.00當量）於DMSO（1.00 mL）中之溶液中添加氟化銫（124 mg，817 µmol，30.1 µL，1.50當量）及(R)-3-(1-胺基乙基)-2-甲基苯甲腈（87.2 mg，544 µmol，1.00當量），且將混合物在130℃下攪拌30分鐘。隨後將混合物冷卻至25℃，用乙酸乙酯（20.0 mL）稀釋，用鹽水（10.0 mL×3）洗滌，且將分離的有機相乾燥且在減壓下濃縮。將殘餘物藉由管柱層析法（SiO₂ ，石油醚/乙酸乙酯＝5/1至2/1）純化，得到呈黃色固體狀之(R )-3-(1-((7-溴-5-氟-4-甲基呔

-1-基)胺基)乙基)-2-甲基苯甲腈（160 mg，401 µmol，73.6%產率）。LCMS [M+1]⁺ : 399.1。Step G: To 7-bromo-1-chloro-5-fluoro-4-methyl

(150 mg, 544 µmol, 1.00 equivalent) Cesium fluoride (124 mg, 817 µmol, 30.1 µL, 1.50 equivalent) and (R)-3-(1-aminoethyl) were added to a solution in DMSO (1.00 mL) Yl)-2-methylbenzonitrile (87.2 mg, 544 µmol, 1.00 equivalent), and the mixture was stirred at 130°C for 30 minutes. The mixture was then cooled to 25°C, diluted with ethyl acetate (20.0 mL), washed with brine (10.0 mL×3), and the separated organic phase was dried and concentrated under reduced pressure. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 5/1 to 2/1) to obtain ( R )-3-(1-((7- Bromo-5-fluoro-4-methyl

-1-yl)amino)ethyl)-2-methylbenzonitrile (160 mg, 401 µmol, 73.6% yield). LCMS [M+1] ⁺ : 399.1.

-1-基)胺基)乙基)-2-甲基苯甲腈（15.0 mg，37.6 µmol，1.00當量）、(R )-六氫-2H ,6H -吡

并[1,2-c ][1,3]

（10.5 mg，48.8 µmol，1.30當量，2 HCl）、碳酸銫（61.2 mg，188 µmol，5.00當量）、RuPhos（3.51 mg，7.51 µmol，0.20當量）及Pd₂ (dba)₃ （3.44 mg，3.76 µmol，0.10當量）於二

烷（1.00 mL）中之混合物脫氣且用氮氣沖洗（3次），且隨後將混合物在氮氣氛圍下在105℃下攪拌2小時。將混合物冷卻至25℃，過濾，且在減壓下濃縮。隨後將殘餘物藉由製備型HPLC[管柱：Phenomenex luna C18 150×25 mm×10 um；移動相：A相：水（0.225%甲酸），B相：乙腈；B%：2%-32%]純化，得到呈灰白色固體狀之3-((R )-1-((5-氟-7-((R )-六氫-2H ,6H -吡

并[1,2-c ][1,3]

-2-基)-4-甲基呔

-1-基)胺基)乙基)-2-甲基苯甲腈（7.70 mg，15.2 µmol，40.5%產率，99.9%純度，甲酸鹽）。LCMS [M+1]⁺ : 461.2。Step H: Add ( R )-3-(1-((7-bromo-5-fluoro-4-methyl

-1-yl)amino)ethyl)-2-methylbenzonitrile (15.0 mg, 37.6 µmol, 1.00 equivalent), ( R )-hexahydro-2 H ,6 H -pyridine

And [1,2- c ][1,3]

(10.5 mg, 48.8 µmol, 1.30 equivalent, 2 HCl), cesium carbonate (61.2 mg, 188 µmol, 5.00 equivalent), RuPhos (3.51 mg, 7.51 µmol, 0.20 equivalent) and Pd ₂ (dba) ₃ (3.44 mg, 3.76 µmol, 0.10 equivalent) in two

The mixture in alkane (1.00 mL) was degassed and flushed with nitrogen (3 times), and then the mixture was stirred at 105°C for 2 hours under a nitrogen atmosphere. The mixture was cooled to 25°C, filtered, and concentrated under reduced pressure. Then the residue was subjected to preparative HPLC [column: Phenomenex luna C18 150×25 mm×10 um; mobile phase: phase A: water (0.225% formic acid), phase B: acetonitrile; B%: 2%-32% ] Purification to obtain 3-(( R )-1-((5-fluoro-7-(( R )-hexahydro-2 H ,6 H -pyridine) as off-white solid

And [1,2- c ][1,3]

-2-yl)-4-methyl

-1-yl)amino)ethyl)-2-methylbenzonitrile (7.70 mg, 15.2 µmol, 40.5% yield, 99.9% purity, formate). LCMS [M+1] ⁺ : 461.2.

-1-基)胺基)乙基)-2-甲基苯甲腈

¹ H NMR (400 MHz, CD ₃ OD) δ = 8.52 (br s, 1H), 7.70 (d, J = 7.6 Hz, 1H), 7.50 (d, J = 7.2 Hz, 1H), 7.41 (d, J = 2.0 Hz, 1H), 7.39-7.33 (m, 1H), 7.25 (t, J = 8.0 Hz, 1H), 5.59-5.51 (m, 1H), 4.11 (br d, J = 13.2 Hz, 1H), 3.96 (br d, J = 12.4 Hz, 1H), 3.92-3.84 (m, 2H), 3.77-3.68 (m, 1H), 3.39-3.33 (m, 1H), 3.21-3.11 (m, 1H), 2.97 (br d, J = 11.6 Hz, 1H), 2.80 (br d, J = 11.6 Hz, 1H), 2.75-2.63 (m, 7H), 2.51-2.35 (m, 3H), 1.62 (d, J = 7.2 Hz, 3H). Example 21-10 ( R )-3-(1-((5-Fluoro-7-(3-hydroxy-3-methylazetidin-1-yl)-4-methyl

-1-yl)amino)ethyl)-2-methylbenzonitrile

-1-基)胺基)乙基)-2-甲基苯甲腈（60.0 mg，150 µmol，1.00當量）、3-甲基氮雜環丁烷-3-醇（27.9 mg，225 µmol，1.50當量，HCl）、碳酸銫（245 mg，751 µmol，5.00當量）、RuPhos（14.0 mg，30.1 µmol，0.20當量）及Pd₂ (dba)₃ （13.8 mg，15.0 µmol，0.10當量）於二

烷（1.00mL）中之混合物脫氣且用氮氣沖洗（3次），且將混合物在氮氣氛圍下在100℃下攪拌2小時。過濾混合物且在減壓下濃縮，且將殘餘物藉由製備型HPLC[管柱：Phenomenex luna C18 150×25 mm×10 um；移動相：A相：水（0.225%甲酸，B相：乙腈；B%：10%-40%]純化，得到呈黃色固體狀之(R )-3-(1-((5-氟-7-(3-羥基-3-甲基氮雜環丁烷-1-基)-4-甲基呔

-1-基)胺基)乙基)-2-甲基苯甲腈（39.0 mg，86.0 µmol，57.3%產率，99.6%純度，甲酸鹽）。LCMS [M+1]⁺ : 406.1。( R )-3-(1-((7-Bromo-5-fluoro-4-methyl

-1-yl)amino)ethyl)-2-methylbenzonitrile (60.0 mg, 150 µmol, 1.00 equivalent), 3-methylazetidine-3-ol (27.9 mg, 225 µmol, 1.50 equivalents, HCl), cesium carbonate (245 mg, 751 µmol, 5.00 equivalents), RuPhos (14.0 mg, 30.1 µmol, 0.20 equivalents) and Pd ₂ (dba) ₃ (13.8 mg, 15.0 µmol, 0.10 equivalents) in two

The mixture in alkane (1.00 mL) was degassed and flushed with nitrogen (3 times), and the mixture was stirred at 100° C. for 2 hours under a nitrogen atmosphere. The mixture was filtered and concentrated under reduced pressure, and the residue was subjected to preparative HPLC [column: Phenomenex luna C18 150×25 mm×10 um; mobile phase: phase A: water (0.225% formic acid, phase B: acetonitrile; B%: 10%-40%] was purified to obtain ( R )-3-(1-((5-fluoro-7-(3-hydroxy-3-methylazetidine-1) as a yellow solid -Yl)-4-methyl

-1-yl)amino)ethyl)-2-methylbenzonitrile (39.0 mg, 86.0 µmol, 57.3% yield, 99.6% purity, formate). LCMS [M+1] ⁺ : 406.1.

¹ H NMR (400 MHz, CD ₃ OD) δ = 8.51 (s, 1H), 7.70 (d, J = 7.6 Hz, 1H), 7.55-7.47 (m, 1H), 7.27 (t, J = 8.0 Hz, 1H), 7.07 (d, J = 2.0 Hz, 1H), 6.87-6.77 (m, 1H), 5.54-5.37 (m, 1H), 4.14-4.07 (m, 2H), 4.07-4.00 (m, 2H) , 2.79-2.65 (m, 6H), 1.68-1.55 (m, 6H). Example 21-11

烷（10.0 mL）中之溶液在氮氣氛圍下在80℃下攪拌10小時。將混合物冷卻至25℃，倒入飽和氟化鉀水溶液（200 mL）中且攪拌30分鐘以得到懸浮液，將該懸浮液過濾，隨後將濾液用乙酸乙酯（200 mL×3）萃取為溶液。將合併之有機層用鹽水（200 mL）洗滌，經硫酸鈉乾燥，過濾，且在減壓下濃縮，得到粗產物3-(1-乙氧基乙烯基)-4-氟-5-(三氟甲基)苯胺（6.00 g，24.1 mmol，1.00當量，粗製），其無需進一步純化即可用於下一步。Step A: Combine 3-bromo-4-fluoro-5-(trifluoromethyl)aniline (4.00 g, 15.5 mmol, 1.00 equivalent), tributyl(1-ethoxyvinyl)tin (5.60 g, 15.5 mmol, 5.23 mL, 1.00 equivalent) and PdCl ₂ (PPh) ₃ (326 mg, 0.47 mmol, 0.03 equivalent) in 1,4-di

The solution in alkane (10.0 mL) was stirred at 80°C for 10 hours under a nitrogen atmosphere. The mixture was cooled to 25°C, poured into a saturated potassium fluoride aqueous solution (200 mL) and stirred for 30 minutes to obtain a suspension, the suspension was filtered, and then the filtrate was extracted with ethyl acetate (200 mL×3) into a solution . The combined organic layer was washed with brine (200 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product 3-(1-ethoxyvinyl)-4-fluoro-5-(tri Fluoromethyl)aniline (6.00 g, 24.1 mmol, 1.00 equivalent, crude), which was used in the next step without further purification.

Step B: Under nitrogen atmosphere, add 3-(1-ethoxyvinyl)-4-fluoro-5-(trifluoromethyl)aniline (6.00 g, 24.1 mmol, 1.00 equivalent, crude) in tetrahydrofuran (20.0 Hydrochloric acid (3.00 M, 8.03 mL, 1.00 equivalent) was added to the solution in mL), and the mixture was stirred at 20°C for 1 hour. The mixture was poured into water (40.0 mL), and then extracted with ethyl acetate (40.0 mL×3). The combined organic layer was washed with brine (40.0 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate = 50/1 to 3/1) to obtain 1-(5-amino-2-fluoro-3- (Trifluoromethyl)phenyl)ethan-1-one (2.00 g, 9.04 mmol).

¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 7.18 (dd, J = 3.0, 5.6 Hz, 1H), 7.08 (dd, J = 3.2, 5.6 Hz, 1H), 5.67 (s, 2H), 2.54 (d, J = 4.4 Hz, 3H).

Step C: To 1-(5-amino-2-fluoro-3-(trifluoromethyl)phenyl)ethan-1-one (2.00 g, 9.04 mmol, 1.00 equivalent) and ( R )-2-methyl To a solution of methyl propane-2-sulfinamide (1.42 g, 11.8 mmol, 1.30 equivalents) in tetrahydrofuran (20.0 mL) was added titanium(IV) isopropoxide (5.14 g, 18.1 mmol, 5.34 mL, 2.00 equivalents) And 1-methoxy-2-(2methoxyethoxy)ethane (4.69 g, 34.9 mmol, 5.00 mL, 3.86 equivalents), and the mixture was stirred at 70° C. for 12 hours under a nitrogen atmosphere. The mixture was then concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate = 30/1 to 1/1) to obtain ( R ) -N as a yellow oil -(1-(5-Amino-2-fluoro-3-(trifluoromethyl)phenyl)ethylene)-2-methylpropane-2-sulfinamide (500 mg, 1.54 mmol, 17.1 %Yield).

¹ H NMR (400 MHz, CDCl ₃ ) δ = 7.07 (br s, 1H), 6.95 (br s, 1H), 3.83 (br s, 2H), 2.74 (br d, J = 2.4 Hz, 3H), 1.31 (s, 9H).

Step D: Under a nitrogen atmosphere at 0°C, to (R)-N-(1-(5-amino-2-fluoro-3-(trifluoromethyl)phenyl)ethylene)-2- To a solution of methylpropane-2-sulfinamide (1.10 g, 3.39 mmol, 1.00 equivalent) in tetrahydrofuran (15.0 mL) was added sodium borohydride (385 mg, 10.2 mmol, 3.00 equivalent) in portions. The mixture was stirred at 0°C for 1 hour, then slowly diluted with saturated aqueous ammonium chloride (40.0 mL), and the resulting mixed solution was extracted with ethyl acetate (30.0 mL×3). The combined organic layer was washed with brine (30.0 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate = 30/1 to 1/1) to obtain ( R ) -N -(1-(5-amino group) as a yellow oil -2-Fluoro-3-(trifluoromethyl)phenyl)ethyl)-2-methylpropane-2-sulfinamide (600 mg, 1.84 mmol, 54.2% yield). LCMS [M+1] ⁺ : 327.0.

¹ H NMR (400 MHz, CDCl ₃ ) δ = 6.97-6.83 (m, 1H), 6.82-6.76 (m, 1H), 4.83-4.69 (m, 1H), 3.71-3.44 (m, 2H), 1.59- 1.50 (m, 3H), 1.25-1.19 (m, 9H). (The ratio of diastereomers is ~2:1).

烷中，5.00 mL，10.9當量），隨後將反應混合物在20℃下攪拌1小時。在減壓下濃縮反應混合物，且藉由緩慢添加飽和碳酸氫鈉水溶液將殘餘物之pH調節至pH＝8。將水溶液用DCM:甲醇（10:1，20.0 mL×5）萃取，將合併之有機相用鹽水（10.0 mL）洗滌，經硫酸鈉乾燥，過濾且在減壓下濃縮，得到呈黃色固體狀之3-(1-胺基乙基)-4-氟-5-(三氟甲基)苯胺（350 mg，1.58 mmol，85.7%產率），其無需進一步純化即可直接使用。Step E: To ( R ) -N -(1-(5-amino-2-fluoro-3-(trifluoromethyl)phenyl)ethyl)-2-methylpropane-2-sulfinamide (600 mg, 1.84 mmol, 1.00 equivalent) in dichloromethane (5.00 mL) was added dropwise HCl (4.00 M in two

In alkane, 5.00 mL, 10.9 equivalents), the reaction mixture was then stirred at 20°C for 1 hour. The reaction mixture was concentrated under reduced pressure, and the pH of the residue was adjusted to pH=8 by slowly adding saturated aqueous sodium bicarbonate solution. The aqueous solution was extracted with DCM: methanol (10:1, 20.0 mL×5), the combined organic phase was washed with brine (10.0 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to obtain a yellow solid 3-(1-aminoethyl)-4-fluoro-5-(trifluoromethyl)aniline (350 mg, 1.58 mmol, 85.7% yield), which was used directly without further purification.

（162 mg，0.63 mmol，1.00當量）及氟化鉀（183 mg，3.15 mmol，73.8 µL，5.00當量）於DMSO（3.00 mL）中之溶液在氮氣氛圍下在130℃下攪拌1小時。將混合物倒入水（20.0 mL）中，且將所得水溶液用乙酸乙酯（20.0 mL×3）萃取。將合併之有機層用鹽水（20.0 mL）洗滌，經硫酸鈉乾燥，過濾，且在減壓下濃縮。將殘餘物藉由製備型HPLC[管柱：Welch Xtimate C18 150×25 mm×5 um；移動相：A相：水（0.05% HCl），B相：乙腈；B%：14%-44%]純化，得到呈白色固體狀之N -(1-(5-胺基-2-氟-3-(三氟甲基)苯基)乙基)-7-溴-4-甲基呔

-1-胺（10.0 mg，18.1 µmol，2.86%產率，80.0%純度）。LCMS [M+1]⁺ : 443.1。Step F: Combine 3-(1-aminoethyl)-4-fluoro-5-(trifluoromethyl)aniline (140 mg, 630 µmol, 1.00 equivalent), 6-bromo-4-chloro-1-methyl Gee

A solution of (162 mg, 0.63 mmol, 1.00 equivalent) and potassium fluoride (183 mg, 3.15 mmol, 73.8 µL, 5.00 equivalent) in DMSO (3.00 mL) was stirred at 130°C for 1 hour under a nitrogen atmosphere. The mixture was poured into water (20.0 mL), and the resulting aqueous solution was extracted with ethyl acetate (20.0 mL×3). The combined organic layer was washed with brine (20.0 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to preparative HPLC [column: Welch Xtimate C18 150×25 mm×5 um; mobile phase: phase A: water (0.05% HCl), phase B: acetonitrile; B%: 14%-44%] Purified to obtain N -(1-(5-amino-2-fluoro-3-(trifluoromethyl)phenyl)ethyl)-7-bromo-4-methyl as a white solid

-1-amine (10.0 mg, 18.1 µmol, 2.86% yield, 80.0% purity). LCMS [M+1] ⁺ : 443.1.

-1-胺（100 mg，226 µmol，1.00當量）藉由SFC[管柱：DAICEL CHIRALPAK AS（250 mm×30 mm，10 um）；移動相：A相：（0.1% NH₄ OH）於甲醇中，B相：CO₂ ；B%：25%-25%]純化，得到第一溶離異構體，為呈白色固體狀之(R )-N -(1-(5-胺基-2-氟-3-(三氟甲基)苯基)乙基)-7-溴-4-甲基呔

-1-胺（20.0 mg，45.1 µmol，20.0%產率）。The racemic N- (1-(5-amino-2-fluoro-3-(trifluoromethyl)phenyl)ethyl)-7-bromo-4-methyl

-1-amine (100 mg, 226 µmol, 1.00 equivalent) by SFC [Column: DAICEL CHIRALPAK AS (250 mm×30 mm, 10 um); mobile phase: Phase A: (0.1% NH ₄ OH) in methanol Among them, phase B: CO ₂ ; B%: 25%-25%] was purified to obtain the first lysomer, which is ( R ) -N -(1-(5-amino-2- Fluoro-3-(trifluoromethyl)phenyl)ethyl)-7-bromo-4-methyl

-1-amine (20.0 mg, 45.1 µmol, 20.0% yield).

-1-胺（20.0 mg，45.1 µmol，1.00當量）、二碳酸二第三丁酯（11.8 mg，54.2 µmol，12.4 µL，1.20當量）及N,N -二甲基吡啶-4-胺（5.51 mg，45.1 µmol，1.00當量）於二氯甲烷（1.00 mL）中之溶液在20℃下攪拌1小時。將混合物倒入水（20.0 mL）中，且隨後用乙酸乙酯（20.0 mL×3）萃取，且將合併之有機層用鹽水（20.0 mL）洗滌，經硫酸鈉乾燥，過濾，且在減壓下濃縮。將殘餘物藉由製備型TLC（矽膠，二氯甲烷/甲醇＝20/1）純化，得到呈灰色固體狀之(R )-(3-(1-((7-溴-4-甲基呔

-1-基)胺基)乙基)-4-氟-5-(三氟甲基)苯基)(第三丁氧基羰基)胺甲酸第三丁酯（15.0 mg，23.3 µmol，51.7%產率）。LCMS [M+3]⁺ : 644.9。Step G: Add ( R ) -N -(1-(5-amino-2-fluoro-3-(trifluoromethyl)phenyl)ethyl)-7-bromo-4-methyl

-1-amine (20.0 mg, 45.1 µmol, 1.00 equivalent), di-tertiary butyl dicarbonate (11.8 mg, 54.2 µmol, 12.4 µL, 1.20 equivalent) and N,N -lutidine-4-amine (5.51 A solution of mg, 45.1 µmol, 1.00 equivalent) in dichloromethane (1.00 mL) was stirred at 20°C for 1 hour. The mixture was poured into water (20.0 mL), and then extracted with ethyl acetate (20.0 mL×3), and the combined organic layer was washed with brine (20.0 mL), dried over sodium sulfate, filtered, and subjected to reduced pressure Down concentrated. The residue was purified by preparative TLC (silica gel, dichloromethane/methanol=20/1) to obtain ( R )-(3-(1-((7-bromo-4-methyl) as a gray solid

-1-yl)amino)ethyl)-4-fluoro-5-(trifluoromethyl)phenyl)(tert-butoxycarbonyl)carbamate (15.0 mg, 23.3 µmol, 51.7%) Yield). LCMS [M+3] ⁺ : 644.9.

-1-基)胺基)乙基)-4-氟-5-(三氟甲基)苯基)(第三丁氧基羰基)胺甲酸第三丁酯（15.0 mg，23.3 µmol，1.00當量）、3-甲基氮雜環丁烷-3-醇（7.46 mg，46.6 µmol，2.00當量，HCl鹽）、RuPhos（2.18 mg，4.66 µmol，0.20當量）、Pd₂ (dba)₃ （2.13 mg，2.33 µmol，0.10當量）及碳酸銫（38.0 mg，0.12 mmol，5.00當量）於1,4-二

烷（2.00 mL）中之溶液在氮氣氛圍下在100℃下攪拌12小時。將混合物冷卻至25℃，倒入水（10.0 mL）中，且將所得水溶液用乙酸乙酯（10.0 mL×3）萃取。將合併之有機層用鹽水（10.0 mL）洗滌，經硫酸鈉乾燥，過濾，且在減壓下濃縮。將殘餘物藉由製備型TLC（二氧化矽，二氯甲烷:甲醇＝10:1）純化，得到呈白色固體狀之(R )-(4-氟-3-(1-((7-(3-羥基-3-甲基氮雜環丁烷-1-基)-4-甲基呔

-1-基)胺基)乙基)-5-(三氟甲基)苯基)胺甲酸第三丁酯（10.0 mg，15.3 µmol，66.0%產率）。LCMS [M+1]⁺ : 550.1。Step H: Add ( R )-(3-(1-((7-bromo-4-methyl

-1-yl)amino)ethyl)-4-fluoro-5-(trifluoromethyl)phenyl)(tert-butoxycarbonyl) carbamate (15.0 mg, 23.3 µmol, 1.00 equivalent) ), 3-methylazetidine-3-ol (7.46 mg, 46.6 µmol, 2.00 equivalent, HCl salt), RuPhos (2.18 mg, 4.66 µmol, 0.20 equivalent), Pd ₂ (dba) ₃ (2.13 mg , 2.33 µmol, 0.10 equivalent) and cesium carbonate (38.0 mg, 0.12 mmol, 5.00 equivalent) in 1,4-di

The solution in alkane (2.00 mL) was stirred at 100°C for 12 hours under a nitrogen atmosphere. The mixture was cooled to 25°C, poured into water (10.0 mL), and the resulting aqueous solution was extracted with ethyl acetate (10.0 mL×3). The combined organic layer was washed with brine (10.0 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (silica dioxide, dichloromethane: methanol = 10:1) to obtain ( R )-(4-fluoro-3-(1-((7-() 3-hydroxy-3-methylazetidin-1-yl)-4-methyl

-1-yl)amino)ethyl)-5-(trifluoromethyl)phenyl)carbamate (10.0 mg, 15.3 µmol, 66.0% yield). LCMS [M+1] ⁺ : 550.1.

-1-基)胺基)乙基)-5-(三氟甲基)苯基)胺甲酸第三丁酯（10.0 mg，15.4 µmol，1.00當量）於二氯甲烷（1.00 mL）中之溶液中逐滴添加TFA（308 mg，2.70 mmol，0.20 mL，175當量），且將反應混合物在20℃下攪拌1小時。隨後將混合物在減壓下濃縮，且將殘餘物藉由製備型HPLC[管柱：3_Phenomenex Luna C18 75×30 mm×3 um；移動相：A相：水（10 mM NH₄ HCO₃ ），B相：乙腈；B%：20%-50%]純化，得到呈灰白色固體狀之(R )-1-(4-((1-(5-胺基-2-氟-3-(三氟甲基)苯基)乙基)胺基)-1-甲基呔

-6-基)-3-甲基氮雜環丁烷-3-醇（1.12 mg，2.41 µmol，15.6%產率，96.6%純度）。LCMS [M+1]⁺ : 450.4。At 20 ℃, to ( R )-(4-fluoro-3-(1-((7-(3-hydroxy-3-methylazetidin-1-yl)-4-methyl

-1-yl)amino)ethyl)-5-(trifluoromethyl)phenyl)carbamic acid tert-butyl ester (10.0 mg, 15.4 µmol, 1.00 equivalent) in dichloromethane (1.00 mL) TFA (308 mg, 2.70 mmol, 0.20 mL, 175 equivalents) was added dropwise, and the reaction mixture was stirred at 20°C for 1 hour. Then the mixture was concentrated under reduced pressure, and the residue was subjected to preparative HPLC [column: 3_Phenomenex Luna C18 75×30 mm×3 um; mobile phase: phase A: water (10 mM NH ₄ HCO ₃ ), B Phase: Acetonitrile; B%: 20%-50%] purified to obtain ( R )-1-(4-((1-(5-amino-2-fluoro-3-(trifluoromethyl) as an off-white solid (Phenyl) Ethyl) Amino)-1-Methyl

-6-yl)-3-methylazetidine-3-ol (1.12 mg, 2.41 µmol, 15.6% yield, 96.6% purity). LCMS [M+1] ⁺ : 450.4.

¹ H NMR (400 MHz, CD ₃ OD) δ = 7.80 (d, J = 8.8 Hz, 1H), 7.10 (d, J = 2.0 Hz, 1H), 6.97 (dd, J = 8.8, 2.0 Hz, 1H) , 6.83-6.80 (m, 1H), 6.67-6.64 (m, 1H), 5.51-5.45 (m, 1H), 3.99-3.95 (m, 2H), 3.89-3.84 (m, 2H), 2.51 (s, 3H), 1.55 (d, J = 7.2 Hz, 3H), 1.51(s, 3H).

SFC: Column: Chiralcel OD-3 50×4.6 mm inner diameter, 3 um; mobile phase: phase A is CO ₂ and phase B is MeOH (0.05% diethylamine); gradient dissolution: MeOH (0.05% diethyl) Amine) in 5% to 40% CO ₂ ; flow rate: 3 ml/min; detector: PDA; column temperature: 35°C; back pressure: 100 Bar. Example A

This example illustrates that an exemplary compound of the present invention binds to SOS1 and prevents the labeled tracer ligand from occupying the SOS1 binding site.

The HTRF displacement assay was used to measure the ability of the compound of formula (I) to bind to SOS1. The recombinant human SOS1 polypeptide (corresponding to amino acid 564-1049, expressed in E. coli as N-terminal StrepII-TEV, C-terminal His tag. MW=60.59 kDa) and an exemplary compound of formula (I) (in DMSO Stock solution) together in a buffer (25 mM HEPES pH 7.5, 25 mM NaCl, 1 mM DTT, 0.01% Brij 35, 0.02% BSA, 0.1% DMSO) incubate. After incubating for 15 minutes at room temperature, a solution consisting of a buffer containing custom Cy5 labeled tracer and monoclonal antibody anti-6HIS Tb cryptate gold (Cisbio 61HI2TLA) was added to the solution containing SOS1 polypeptide and formula (I ) In a solution of an exemplary compound. After incubating for 1 hour at room temperature, the HTRF signal was measured using an Envision disk reader (Perkin Elmer) according to the manufacturer's instructions. Excitation is in the range of 245-395 nm, and emission 1 is detected at (657.5-672.5) nm, and emission 2 is detected at (606.5-623.5) nm. Use the following formula to calculate the HTRF ratio: [Transmit 1 / Transmit 2] * 10000.

The background signal is calculated from the well without the addition of protein. Relative to the DMSO control, the background subtracted signal is converted to% binding. Use GraphPad Prism 4 software to analyze the data, which is set to: "S-shaped dose response (variable slope)"; Hill slope is 4 parameters (constraint: bottom=constant equal to 0; top=must be less than 120).

The results are shown in Table 21. Key: ND=not determined. Table 21 Inhibition of the labeled tracer from binding to SOS1 by an exemplary compound of formula (I) Instance number IC ₅₀ ( nM ) Instance number IC ₅₀ ( nM ) 1-1 61 1-21 1.8 1-2 35 1-22 1.7 1-3 2.3 1-23 2.4 1-4 2.1 2-1 Not sure 1-5 2.5 2-2 13 1-6 6.8 2-3 10 1-7 2.1 2-4 47.6 1-8 1.6 3-1 5.2 1-9 2.3 3-2 3.6 1-10 2.3 3-3 2.3 1-11 ＞10000 3-4 129 1-12 664 3-5 4 1-13 31 3-6 133 1-14 25 4-1 6.5 1-15 2.7 4-2 6.3 1-16 1.6 4-3 4.5 1-17 6.2 4-4 2.5 1-18 0.73 5-1 7.2 1-19 2.6 5-2 5.9 1-20 145 Example B

This example illustrates that an exemplary compound of the present invention binds to SOS1 and prevents the labeled tracer ligand from occupying the SOS1 binding site.

The HTRF displacement assay was used to measure the ability of the compound of formula (I) to bind to SOS1. Recombinant human SOS1 polypeptide (corresponding to amino acid 560-1049, in E. coli with N-terminal His-TEV-AviTag-SOS1 (MW=59.4 kDa) and streptavidin (CisBio) labeled with lanthanide elements Performance) and the exemplary compound of formula (I) (in DMSO stock solution) in buffer (25 mM HEPES pH 7.5, 25 mM NaCl, 1 mM DTT, 0.01% Brij 35, 0.02% BSA, 0.1% DMSO) Nurture. After incubating for 10-15 minutes at room temperature, add the solution containing the customized Cy5 labeled tracer and monoclonal antibody anti-6HIS Tb cryptate gold (Cisbio 61HI2TLA) in the buffer to the SOS1 polypeptide and formula ( I) In solution in exemplary compounds. After incubating for 1 hour at room temperature, the HTRF signal was measured using a Clairostar disc reader (BMG Labtech) according to the manufacturer's instructions. Excitation filter EX-TR is used, and emission 1 is detected at 650-610 nm and emission 2 is detected at 620-610 nm. Use the following formula to calculate the HTRF ratio: [Transmit 1 / Transmit 2] * 10000.

Calculate the background signal from the wells with 10 µM inhibitor, which is known to inhibit 100% at this concentration. Relative to the DMSO control, the background subtracted signal is converted to% binding. Use the Morrison equation for competitive binding to analyze the data with XLFIT software (IDBS), and generate the Ki of the compound of formula (I).

The results are shown in Table 22. Table 22 Inhibition of the labeled tracer from binding to SOS1 by an exemplary compound of formula (I) Instance number K _i ( nM ) Instance number K _i ( nM ) 1-24 12-14 0.55 1-25 0.95 12-15 0.25 1-26 1.16 12-16 0.87 1-27 12-17 0.46 1-28 0.17 12-18 0.62 1-29 0.51 12-19 1.00 1-30 12-20 1.60 1-31 12-21 1.32 1-32 0.42 12-22 1.24 1-33 0.70 12-23 1.05 1-34 0.45 12-24 1.24 1-35 0.47 12-25 2.41 1-36 12-26 0.45 1-37 0.25 12-27 2.81 1-38 0.50 12-28 1.53 1-39 12-29 1.67 1-40 0.27 12-30 2.63 1-41 12-31 1.02 1-42 12-32 0.97 1-43 1.36 12-33 0.30 1-44 0.42 12-34 4.24 1-45 0.42 12-35 3.78 1-46 12-36 0.99 1-47 2.08 12-37 0.85 1-48 0.56 12-38 1.29 1-49 12-39 0.91 1-50 12-40 0.64 2-5 1.78 12-41 40.24 2-6 2.10 12-42 0.79 2-7 12-43 3.38 2-8 2.99 12-44 1.16 2-9 12-45 3.78 2-10 1.72 12-46 0.92 2-11 2.83 12-47 38.69 2-12 5.75 12-48 16.96 5-3 390.50 12-49 39.66 5-4 47.90 12-50 3.02 6-1 0.11 12-51 0.79 6-2 1.35 12-52 1.06 6-3 0.02 12-53 0.83 6-4 0.11 12-54 5.37 6-5 0.12 12-55 3.10 6-6 0.11 12-56 31.09 6-7 0.29 12-57 92.17 6-8 39.20 12-58 14.62 6-9 0.24 12-59 0.47 6-10 ＜0.01 12-60 0.25 6-11 9.10 12-61 1.68 6-12 0.88 12-62 6-13 0.29 12-63 0.83 6-14 5.51 12-64 0.51 6-15 12.55 12-65 0.72 6-16 10.07 12-66 2.10 6-17 56.45 12-67 0.36 6-18 316.70 12-68 0.37 6-19 2.32 12-69 0.93 7-1 0.40 12-70 0.68 7-2 0.33 12-71 4.48 7-3 0.32 12-72 4.39 7-4 0.47 12-73 1.67 7-5 0.82 12-74 10.48 7-6 1.41 12-75 13.99 7-7 0.92 12-76 1.06 8-1 1.38 12-77 28.51 8-2 3.74 12-78 2.66 9-1 109.00 12-79 36.27 9-2 0.93 12-80 37.38 10-1 3.07 12-81 28.98 10-2 14.90 12-82 20.95 10-3 0.71 12-83 50.64 10-4 0.08 12-84 43.44 10-5 ＜0.01 12-85 27.62 10-6 0.64 12-86 0.98 10-7 0.07 12-87 3.17 10-8 0.09 12-88 2.03 10-9 0.05 12-89 0.25 10-10 0.01 12-90 10-11 0.01 12-91 10-12 0.40 12-92 10-13 0.49 12-93 10-14 12-94 10-15 12-95 10-16 7.75 12-96 10-17 12-97 10-18 1.41 12-98 19.04 10-19 0.28 12-99 0.93 10-20 12-100 1.07 10-21 12-101 1.45 10-22 0.45 12-102 0.25 10-23 0.42 12-103 10.93 10-24 1.34 12-104 6.10 10-25 1.47 12-105 10.89 10-26 0.47 12-106 11.05 10-27 0.46 12-107 35.65 10-28 0.45 12-108 22.11 10-29 0.39 12-109 2.61 10-30 0.41 12-110 3.54 10-31 0.35 12-111 8.09 10-32 0.20 12-112 2.20 10-33 0.69 12-113 2.62 10-34 0.56 12-114 69.26 10-35 0.31 12-115 1.66 10-36 0.23 12-116 10-37 0.24 12-117 10-38 0.71 12-118 10-39 1.49 12-119 10-40 0.43 12-120 49.78 10-41 0.52 12-121 39.24 10-42 0.31 12-122 170.30 10-43 1.13 12-123 50.43 10-44 0.51 12-124 64.46 10-45 2.16 12-125 10.29 10-46 1.13 12-126 14.04 10-47 1.19 12-127 6.08 10-48 1.35 12-128 10-49 0.56 12-129 10-50 3.74 12-130 10-51 1.40 12-131 3.6 10-52 44.45 12-132 11 10-53 12-133 11.5 10-54 1.34 12-134 7.1 10-55 0.76 13-1 2.77 10-56 1.59 13-2 191.10 10-57 0.75 13-3 12.23 10-58 5.78 14-1 8.97 10-59 30.91 14-2 10-60 2.00 14-3 14.46 10-61 1.61 14-4 8.55 10-62 0.90 14-5 2.54 10-63 0.54 14-6 2.56 10-64 1.70 15-1 3.37 10-65 0.95 15-2 0.42 10-66 0.78 15-3 0.94 10-67 2.57 16-1 14.42 10-68 0.75 16-2 19.40 10-69 3.07 16-3 13.41 10-70 0.89 16-4 10.41 10-71 0.39 16-5 5.50 10-72 46.10 16-6 6.50 10-73 0.63 16-7 78.79 10-74 4.26 16-8 21.24 10-75 6.51 16-9 35.62 10-76 3.44 16-10 81.01 10-77 0.75 16-11 107.50 10-78 1.16 16-12 9.58 10-79 4.15 16-13 25.82 10-80 5.75 16-14 1.71 10-81 0.90 17-1 4.33 10-82 0.86 17-2 12.47 10-83 4.54 17-3 12.80 10-84 2.01 17-4 14.39 10-85 0.78 18-1 0.98 10-86 1.51 18-2 5.27 10-87 18-3 1.37 11-1 0.01 18-4 1.64 11-2 ＜0.01 19-1 6.16 11-3 ＜0.01 19-2 95.00 11-4 0.01 19-3 19.28 11-5 0.01 20-1 0.92 11-6 0.42 20-2 0.75 12-1 0.20 20-3 0.92 12-2 0.60 20-5 0.40 12-3 0.74 21-1 2.93 12-4 21-2 1.67 12-5 21-3 14.41 12-6 0.87 21-4 13.69 12-7 0.40 21-5 1.34 12-8 1.14 21-6 0.93 12-9 0.47 21-7 0.71 12-10 1.78 21-8 3.17 12-11 8.76 21-9 2.10 12-12 21.64 21-10 5.73 12-13 1.57 21-11

As shown in Table 22, the exemplary compounds of the present invention effectively inhibit the binding of the SOS1 labeled tracer to the SOS1 protein. Example C

This example illustrates that the exemplary compound of the present invention binds to SOS1 and inhibits the SOS1-mediated nucleotide exchange between mantGDP (preloaded into human KRAS) and GTP in recombinant human KRAS.

Fluorescence assay was used to measure the ability of the exemplary compound of formula (I) to bind to SOS1 and inhibit the nucleotide exchange between mantGDP and GTP in recombinant human KRAS. Recombinant human SOS1 polypeptide (corresponding to amino acid 564-1049, expressed in E. coli with a C-terminal StrepII tag. MW=60.59 kDa) and an exemplary compound of formula (I) (in DMSO stock solution) were buffered Incubate in solution (40 mM HEPES 7.4, 10 mM MgCl2, 1 mM DTT, 0.002% Triton X100, 0.1% DMSO) at room temperature for 15 minutes. The pre-loaded mantGDP recombinant human KRAS polypeptide (corresponding to amino acid 2-169, expressed in E. coli as an N-terminal TEV cleavable his-tag. MW 21.4 kDa) and GTP mixture in a buffer (40 mM HEPES 7.4, 10 mM MgCl2, 1 mM DTT 0.002%, Triton X100, 0.1% DMSO) were incubated at room temperature for 5 minutes, and then added to the SOS1/compound mixture. According to the manufacturer's instructions, use a Clariostar disc reader (excitation 370 ± 15 nm, emission 450 ± 20 nm) at room temperature to monitor the progress of the reaction for 60 minutes. Use Clariostar software to calculate the slope of the linear part of the progress curve. The typical analysis interval is 8-30 minutes. The background signal is calculated from the well without added protein. Relative to the DMSO control, the background subtracted signal was converted to% activity. Use GraphPad Prism 4 software to analyze the data, which is set to: "S-shaped dose response (variable slope)"; Hill slope is 4 parameters (constraint: bottom=constant equal to 0; top=must be less than 120).

Fluorescent readings compound of Example IC shown formula (I) of ₅₀ shown in Table 23. Table 23 Instance number IC ₅₀ ( nM ) 1-1 35 1-2 20 1-4 7 1-5 9 1-6 12 1-7 8 1-8 8 1-9 7 1-10 9

As shown in Table 23, the exemplary compounds of the present invention can effectively inhibit SOS1-mediated GTP nucleotide exchange by blocking mant-GDP exchange. Instance D

This example illustrates that the exemplary compound of the present invention prevents KRas-mediated GTP nucleotide exchange mediated by SOS1 to inhibit KRas activity, thereby inhibiting the production of downstream effector pERK.

MKN1 cells (15,000/w) or H358 (30,000/w) were seeded in a black transparent flat-bottomed 96-well cell culture dish (Corning, #3904), and incubated at 37°C overnight. On the first day of the assay, the compound of formula (I) with an initial concentration of 10 µm was added to the cells, and the compounds were diluted 3 times in sequence, and a total of 9 concentrations were added. The cells are incubated with the compound dissolved in DMSO at 37°C for about 0.5-1 hour. Fix the cells immediately by adding 50 µL of 4% formaldehyde to all wells in the fume hood, and incubate the plate at room temperature for 20 minutes. Discard the formaldehyde from the plate, and add 150 µL of ice methanol to permeabilize the cells at -20°C for 10 minutes. Discard the methanol from each dish by tapping the dish with a paper towel, and discard any liquid remaining in the dish. Then the cells were blocked with 0.05% Tween and 150 µL Odyssey blocking buffer (LI-COR Biosciences#927-50010) on a shaker for 1 hour at room temperature. Discard the blocking buffer, and add 50 µL of primary antibody pERK (Cell Signal Technology #9101L; rabbit, 1:500) and GapDH (Millipore#MAB34; mouse, 1:5000) diluted in Odyssey blocking buffer. The plate was incubated overnight at 4°C on a shaker.

On the second day of the assay, remove the primary antibody solution. Each plate was washed 3 times with 150 µL 1x PBST (PBS+0.1% Tween 20), and 50 µL secondary antibodies: anti-rabbit (LI-COR Biosciences#926-32211) and anti-mouse (LI-COR Biosciences#) 68070) Incubate, dilute with Tween in Odyssey blocking buffer at a ratio of 1:800 at room temperature, and incubate on a shaker for 2 hours (protected from light). The secondary antibody solution was removed, and each dish was washed 3 times with PBST. Discard any remaining liquid and use a Licor Odyssey machine to image the disc with a focal length set to 3 mm and filters at 800 nm and 700 nm according to the manufacturer's instructions. Divide the GAPDH normalized scan value of each well by the average of the carrier wells to obtain the percentage of pERK inhibition. Then use Graph pad Prism software to calculate IC ₅₀ value.

The results are shown in Table 24. Key: ND=not determined. Table 24 Instance number IC ₅₀ ( nM ) Instance number IC ₅₀ ( nM ) 1 ̶ 2 1050 11 ̶ 1 10 1 ̶ 3 52 11 ̶ 2 27 1 ̶ 4 134 11 ̶ 3 48 1 ̶ 5 60 11 ̶ 4 25 1 ̶ 6 54 11 ̶ 5 12 1 ̶ 7 31 11 ̶ 6 55 1 ̶ 8 66 12 ̶ 1 5 1 ̶ 9 90 12 ̶ 2 9 1 ̶ 10 132 12 ̶ 3 30 1 ̶ 11 ＞10,000 12 ̶ 4 370 1 ̶ 12 3965 12 ̶ 5 850 1 ̶ 13 378 12 ̶ 6 522 1 ̶ 14 165 12 ̶ 7 66 1 ̶ 15 twenty four 12 ̶ 8 38 1 ̶ 16 348 12 ̶ 9 10 1 ̶ 17 414 12 ̶ 10 46 1 ̶ 18 58 12 ̶ 11 142 1 ̶ 19 116 12 ̶ 12 249 1 ̶ 20 3739 12 ̶ 13 39 1 ̶ 21 187 12 ̶ 14 17 1 ̶ 22 70 12 ̶ 15 17 1 ̶ 23 58 12 ̶ 16 11 1 ̶ 24 25 12 ̶ 17 17 1 ̶ 25 47 12 ̶ 18 37 1 ̶ 26 57 12 ̶ 19 59 1 ̶ 27 61 12 ̶ 20 62 1 ̶ 28 61 12 ̶ 21 57 1 ̶ 29 71 12 ̶ 22 89 1 ̶ 30 79 12 ̶ 23 46 1 ̶ 31 83 12 ̶ 24 38 1 ̶ 32 101 12 ̶ 25 35 1 ̶ 33 109 12 ̶ 26 27 1 ̶ 34 119 12 ̶ 27 14 1 ̶ 35 123 12 ̶ 28 17 1 ̶ 36 125 12 ̶ 29 16 1 ̶ 37 131 12 ̶ 30 54 1 ̶ 38 136 12 ̶ 31 70 1 ̶ 39 170 12 ̶ 32 18 1 ̶ 40 171 12 ̶ 33 55 1 ̶ 41 195 12 ̶ 34 51 1 ̶ 42 201 12 ̶ 35 35 1 ̶ 43 216 12 ̶ 36 12 1 ̶ 44 235 12 ̶ 37 32 1 ̶ 45 335 12 ̶ 38 97 1 ̶ 46 341 12 ̶ 39 75 1 ̶ 47 349 12 ̶ 40 twenty four 1 ̶ 48 364 12 ̶ 41 1274 1 ̶ 49 426 12 ̶ 42 27 1 ̶ 50 453 12 ̶ 43 44 twenty one 308 12 ̶ 44 38 twenty two 118 12 ̶ 45 250 twenty three 45 12 ̶ 46 37 twenty four 1929 12 ̶ 47 307 2 ̶ 5 82 12 ̶ 48 114 2 ̶ 6 83 12 ̶ 49 161 2 ̶ 7 142 12 ̶ 50 25 2 ̶ 8 148 12 ̶ 51 48 2 ̶ 9 172 12 ̶ 52 60 2 ̶ 10 223 12 ̶ 53 47 2 ̶ 11 243 12 ̶ 54 45 2 ̶ 12 304 12 ̶ 55 59 3 ̶ 1 128 12 ̶ 56 301 3 ̶ 2 69 12 ̶ 57 1857 3 ̶ 3 20 12 ̶ 58 38 3 ̶ 4 1059 12 ̶ 59 19 3 ̶ 5 4218 12 ̶ 60 twenty four 3 ̶ 6 4259 12 ̶ 61 twenty one 4 ̶ 1 327 12 ̶ 62 4 ̶ 2 131 12 ̶ 63 4 ̶ 3 71 12 ̶ 64 29 4 ̶ 4 130 12 ̶ 65 16 5 ̶ 1 669 12 ̶ 66 77 5 ̶ 2 120 12 ̶ 67 5 ̶ 3 Not sure 12 ̶ 68 5 ̶ 4 1623 12 ̶ 69 6 ̶ 1 79 12 ̶ 70 13 6 ̶ 2 100 12 ̶ 71 6 ̶ 3 12 12 ̶ 72 19 6 ̶ 4 47 12 ̶ 73 6 ̶ 5 10 12 ̶ 74 6 ̶ 6 40 12 ̶ 75 87 6 ̶ 7 74 12 ̶ 76 56 6 ̶ 8 Not sure 12 ̶ 77 6 ̶ 9 48 12 ̶ 78 94 6 ̶ 10 271 12 ̶ 79 173 6 ̶ 11 31 12 ̶ 80 295 6 ̶ 12 30 12 ̶ 81 6 ̶ 13 20 12 ̶ 82 330 6 ̶ 14 320 12 ̶ 83 749 6 ̶ 15 172 12 ̶ 84 280 6 ̶ 16 333 12 ̶ 85 602 6 ̶ 17 412 12 ̶ 86 6 ̶ 18 3696 12 ̶ 87 6 ̶ 19 242 12 ̶ 88 7 ̶ 1 79 12 ̶ 89 7 ̶ 2 73 12 ̶ 90 7 ̶ 3 28 12 ̶ 91 7 ̶ 4 14 12 ̶ 92 7 ̶ 5 110 12 ̶ 93 7 ̶ 6 110 12 ̶ 94 7 ̶ 7 115 12 ̶ 95 8 ̶ 1 164 12 ̶ 96 8 ̶ 2 605 12 ̶ 97 9 ̶ 1 ＞10,000 12 ̶ 98 9 ̶ 2 176 12 ̶ 99 10 ̶ 1 183 12 ̶ 100 10 ̶ 2 1366 12 ̶ 101 twenty two 10 ̶ 3 85 12 ̶ 102 10 ̶ 4 14 12 ̶ 103 107 10 ̶ 5 108 12 ̶ 104 92 10 ̶ 6 twenty one 12 ̶ 105 97 10 ̶ 7 twenty two 12 ̶ 106 114 10 ̶ 8 34 12 ̶ 107 10 ̶ 9 54 12 ̶ 108 10 ̶ 10 17 12 ̶ 109 10 ̶ 11 twenty two 12 ̶ 110 10 ̶ 12 29 12 ̶ 111 10 ̶ 13 39 12 ̶ 112 10 ̶ 14 1150 12 ̶ 113 10 ̶ 15 844 12 ̶ 114 10 ̶ 16 325 12 ̶ 115 19 10 ̶ 17 2629 12 ̶ 116 10 ̶ 18 291 12 ̶ 117 10 ̶ 19 69 12 ̶ 118 10 ̶ 20 1646 12 ̶ 119 10 ̶ 21 444 12 ̶ 120 10 ̶ 22 38 12 ̶ 121 10 ̶ 23 19 12 ̶ 122 10 ̶ 24 69 12 ̶ 123 10 ̶ 25 103 12 ̶ 124 856 10 ̶ 26 164 12 ̶ 125 114 10 ̶ 27 154 12 ̶ 126 10 ̶ 28 161 12 ̶ 127 10 ̶ 29 70 12 ̶ 128 10 ̶ 30 48 12 ̶ 129 10 ̶ 31 3585 12 ̶ 130 10 ̶ 32 28 12 ̶ 131 28 10 ̶ 33 275 12 ̶ 132 76 10 ̶ 34 136 12 ̶ 133 97 10 ̶ 35 1000 12 ̶ 134 10 ̶ 36 79 13 ̶ 1 149 10 ̶ 37 55 13 ̶ 2 2068 10 ̶ 38 29 13 ̶ 3 195 10 ̶ 39 110 14 ̶ 1 68 10 ̶ 40 11 14 ̶ 2 139 10 ̶ 41 30 14 ̶ 3 10 ̶ 42 43 14 ̶ 4 89 10 ̶ 43 138 14 ̶ 5 70 10 ̶ 44 53 14 ̶ 6 142 10 ̶ 45 57 15 ̶ 1 28 10 ̶ 46 157 15 ̶ 2 8 10 ̶ 47 55 15 ̶ 3 34 10 ̶ 48 75 16 ̶ 1 245 10 ̶ 49 107 16 ̶ 2 284 10 ̶ 50 205 16 ̶ 3 208 10 ̶ 51 39 16 ̶ 4 371 10 ̶ 52 286 16 ̶ 5 71 10 ̶ 53 16 ̶ 6 239 10 ̶ 54 48 16 ̶ 7 2904 10 ̶ 55 76 16 ̶ 8 93 10 ̶ 56 26 16 ̶ 9 643 10 ̶ 57 46 16 ̶ 10 919 10 ̶ 58 52 16 ̶ 11 10 ̶ 59 570 16 ̶ 12 10 ̶ 60 961 16 ̶ 13 ＞10000 10 ̶ 61 57 16 ̶ 14 37 10 ̶ 62 76 17 ̶ 1 30 10 ̶ 63 50 17 ̶ 2 50 10 ̶ 64 513 17 ̶ 3 188 10 ̶ 65 twenty three 17 ̶ 4 116 10 ̶ 66 108 18 ̶ 1 128 10 ̶ 67 44 18 ̶ 2 380 10 ̶ 68 36 18 ̶ 3 10 ̶ 69 39 18 ̶ 4 41 10 ̶ 70 15 19 ̶ 1 156 10 ̶ 71 19 19 ̶ 2 779 10 ̶ 72 466 19 ̶ 3 114 10 ̶ 73 49 20 ̶ 1 11 10 ̶ 74 65 20 ̶ 2 8 10 ̶ 75 56 20 ̶ 3 16 10 ̶ 76 85 20 ̶ 5 10 ̶ 77 102 21 ̶ 1 77 10 ̶ 78 114 21 ̶ 2 137 10 ̶ 79 16 21 ̶ 3 221 10 ̶ 80 21 ̶ 4 118 10 ̶ 81 21 ̶ 5 1114 10 ̶ 82 52 21 ̶ 6 176 10 ̶ 83 21 ̶ 7 26 10 ̶ 84 21 ̶ 8 90 10 ̶ 85 18 21 ̶ 9 54 10 ̶ 86 twenty one 21 ̶ 10 58 10 ̶ 87 21 ̶ 11

The results in Table 24 indicate that the compounds of the present invention can effectively inhibit KRas-mediated activation and pERK formation, thereby blocking intracellular KRas-mediated signal transduction. Example E

This example illustrates that the exemplary compound of the present invention prevents KRas-mediated GTP nucleotide exchange mediated by SOS1 in the SOS1 N233Y mutant cell line to inhibit KRas activity, thereby inhibiting the production of downstream effector Perk.

The study used three cell lines with SOS1 N233Y activating mutations, LXF289 (DSMZ, Leibniz Institute, Germany), RL95-2 (ATCC CRL-1671); and OCI AML-5 (DSMZ, Leibniz Research, Germany) Place). SOS1 N233Y mutant cells (15,000/w) were seeded in a black transparent flat-bottomed 96-well cell culture dish (Corning, #3904), and incubated at 37°C overnight. On the first day of the assay, the compound of formula (I) with an initial concentration of 10 µm was added to the cells, and the compounds were diluted 3 times in sequence, and a total of 9 concentrations were added. The cells were incubated with the compound dissolved in DMSO at 37°C for 1 hour. Fix the cells immediately by adding 50 µL of 4% formaldehyde to all wells in the fume hood, and incubate the plate at room temperature for 20 minutes. Discard the formaldehyde from the plate, and add 150 µL of ice methanol to permeabilize the cells at -20°C for 10 minutes. By tapping the plate with a paper towel, the methanol is discarded from each dish, and any liquid remaining in the dish is discarded. Then the cells were blocked with 0.05% Tween and 150 µL Odyssey blocking buffer (LI-COR Biosciences#927-50010) on a shaker for 1 hour at room temperature. Discard the blocking buffer, and add 50 µL of primary antibody pERK (Cell Signal Technology #9101L; rabbit, 1:500) and GapDH (Millipore#MAB34; mouse, 1:5000) diluted in Odyssey blocking buffer. The plate was incubated overnight at 4°C on a shaker.

On the second day of the assay, remove the primary antibody solution. Each plate was washed 3 times with 150 µL 1x PBST (PBS+0.1% Tween 20), and 50 µL secondary antibodies: anti-rabbit (LI-COR Biosciences#926-32211) and anti-mouse (LI-COR Biosciences#) 68070) Incubate, dilute with Tween in Odyssey blocking buffer at a ratio of 1:800 at room temperature, and incubate on a shaker for 2 hours (protected from light). The secondary antibody solution was removed, and each dish was washed 3 times with PBST. Discard any remaining liquid and use a Licor Odyssey machine to image the disc with a focal length set to 3 mm and filters at 800 nm and 700 nm according to the manufacturer's instructions. Divide the GAPDH normalized scan value of each well by the average of the carrier wells to obtain the percentage of pERK inhibition. Then use Graph pad Prism software to calculate IC ₅₀ value.

The results are shown in Table 25. Table 25 Cell line Instance number IC ₅₀ ( nM ) LXF289 6-10 294 6-11 41 RL95-2 6-10 214 6-11 20 OCI AML-5 6-10 333 6-11 32

The results in Table 25 indicate that the compounds of the present invention can effectively inhibit KRas-mediated activation and pERK formation in cells with SOS1 activating mutations, thereby blocking intracellular KRas-mediated signal transduction driven by increased SOS1 activity. Example F

This example illustrates that the exemplary compound of the present invention prevents the increase of KRas-mediated GTP nucleotide exchange in NF-1 mutant cell lines mediated by SOS1 to inhibit KRas activity, thereby inhibiting the production of downstream effector pERK.

In these studies, two cell lines with activating mutations in the NF-1 gene, Kasuma-1 (ATCC CRL-2724); and NCI-H1435 (ATCC CRL-5870), were used. NF-1 mutant cells (15,000/w) were seeded in a black transparent flat-bottomed 96-well cell culture dish (Corning, #3904), and incubated at 37°C overnight. On the first day of the assay, the compound of formula (I) with an initial concentration of 10 µm was added to the cells, and the compounds were diluted 3 times in sequence, and a total of 9 concentrations were added. The cells were incubated with the compound dissolved in DMSO at 37°C for 1 hour. Fix the cells immediately by adding 50 µL of 4% formaldehyde to all wells in the fume hood, and incubate the plate at room temperature for 20 minutes. Discard the formaldehyde from the plate, and add 150 µL of ice methanol to permeabilize the cells at -20°C for 10 minutes. Discard the methanol from each dish by tapping the dish with a paper towel, and discard any liquid remaining in the dish. Then the cells were blocked with 0.05% Tween and 150 µL Odyssey blocking buffer (LI-COR Biosciences#927-50010) on a shaker for 1 hour at room temperature. Discard the blocking buffer, and add 50 µL of primary antibody pERK (Cell Signal Technology #9101L; rabbit, 1:500) and GapDH (Millipore#MAB34; mouse, 1:5000) diluted in Odyssey blocking buffer. The plate was incubated overnight at 4°C on a shaker.

On the second day of the assay, remove the primary antibody solution. Each plate was washed 3 times with 150 µL 1x PBST (PBS + 0.1% Tween 20), and 50 µL secondary antibodies: anti-rabbit (LI-COR Biosciences#926-32211) and anti-mouse (LI-COR Biosciences#) 68070) Incubate, dilute with Tween in Odyssey blocking buffer at a ratio of 1:800 at room temperature, and incubate on a shaker for 2 hours (protected from light). The secondary antibody solution was removed, and each dish was washed 3 times with PBST. Discard any remaining liquid and use a Licor Odyssey machine to image the disc with a focal length set to 3 mm and filters at 800 nm and 700 nm according to the manufacturer's instructions. Divide the GAPDH normalized scan value of each well by the average of the carrier wells to obtain the percentage of pERK inhibition. Then use Graph pad Prism software to calculate IC ₅₀ value.

The results are shown in Table 26. Table 26 Cell line Instance number IC ₅₀ ( nM ) Kasumi 6-10 902 6-11 97 H1435 6-3 25 6-4 51 6-5 9 6-6 29 6-9 52 6-10 542 6-11 65 6-12 63 7-3 55 7-4 83 10-4 33 10-6 75 10-7 87 10-8 94 10-9 152 10-10 15 10-11 63 11-1 6 11-2 17 11-3 62 11-4 19

The results in Table 26 show that the compounds of the present invention can effectively inhibit KRas-mediated activation and pERK formation in cells with NF-1 activating mutations, thereby blocking the increased SOS1 activity driven by NF-1 KRas-mediated signal transduction in cells.

Although the present invention has been described in conjunction with its specific specific examples, it should be understood that it can be further modified, and this application is intended to cover any changes, uses or modifications of the present invention, which generally follow the principles of the present invention and are included in Such deviations from the present invention that occur within the scope of known or customary practice in the technology to which the present invention belongs can be applied to the basic features set forth above, and follow the scope of the attached patent application.

without

without

Claims (88)

A compound of formula (I):

Formula (I) or a pharmaceutically acceptable salt thereof, wherein: R ¹ is hydrogen, hydroxyl, C1-C6 alkyl, alkoxy, -N(R ⁶ ) ₂ , -NR ⁶ C(O)R ⁶ , -C(O)N(R ⁶ ) ₂ , -SO ₂ alkyl, -SO ₂ NR ⁶ alkyl, cycloalkyl, -Q-heterocyclyl, aryl or heteroaryl, wherein the cycloalkyl , The heterocyclic group, the aryl group and the heteroaryl group are each ^{substituted with one or more R 2} or LR ² as appropriate; each Q is independently a bond, O or NR ⁶ ; X is N or CR ⁷ ; each R ^{2 are} independently C1-C3 alkyl, pendant oxy, hydroxyl, halogen, cyano, hydroxyalkyl, haloalkyl, alkoxy, -C(O)N(R ⁶ ) ₂ , -N(R ⁶ ) ₂ , -SO ₂ alkyl, -NR ⁶ C(O)C1-C3 alkyl, -C(O)cycloalkyl, -C(O)C1-C3 alkyl, -C(O)heterocyclyl , aryl, heteroaryl or heterocyclyl, wherein the cycloalkyl, the heterocyclic group, the aryl group, the heteroaryl group or the heterocyclic group are each optionally substituted with one or more R ^11; R ³ Is hydrogen, C1-C6 alkyl, alkoxy, -N(R ¹⁰ ) ₂ , -LN(R ¹⁰ ) ₂ , cycloalkyl, haloalkyl or heterocyclic group, wherein the C1-C6 alkyl, the The cycloalkyl group and the heterocyclic group are each ^{substituted by one or more R 9} as appropriate; Y is a bond or a heteroaryl group; R ⁴ is an aryl group or a heteroaryl group, each of which is optionally substituted by one or more R ⁵ Substitution; each R ^{5 is} independently hydroxy, halogen, cyano, hydroxyalkyl, alkoxy, C1-C3 alkyl, haloalkyl, haloalkyl -OH, -N(R ⁶ ) ₂ , -LN( R ⁶ ) ₂ or -SO ₂ alkyl; L is C1-C3 alkylene; each R ^{6 is} independently hydrogen, C1-C3 alkyl, haloalkyl or cycloalkyl; R ⁷ is hydrogen, cyano, CF ₃ , F or alkoxy; R ⁸ is C1-C2 alkyl or halo-C1-C2 alkyl; each R ^{9 is} independently hydroxyl, halogen, amino, cyano, alkoxy or C1-C3 Alkyl; each R ^{10 is} independently hydrogen, C1-C3 alkyl or cycloalkyl; each R ^{11 is} independently C1-C3 alkyl, halogen or haloalkyl; and R ¹² is hydrogen, halogen or C1-C3 alkyl. Such as the compound of claim 1, wherein X is N. Such as the compound of claim 1, wherein X is CR ⁷ . The compound of claim 1, wherein R ¹ is an alkoxy group or -Q-heterocyclic group, wherein the heterocyclic group is optionally substituted with one or more R ² or LR ² . The compound of claim 4, wherein R ¹ is -Q-heterocyclic group, and wherein Q is a bond or -O-, and the heterocyclic group is

Linyl, Piper

Piperidine

ketone. The compound of claim 5, wherein R ¹ is -Q-heterocyclic group, and wherein the heterocyclic group is bridged

Linyl, bridged piperazine

Bridged piperazine

ketone. The compound of claim 4, wherein R ¹ is -Q-heterocyclic group, and wherein the heterocyclic group is a spiro ring system containing two or more rings. The compound of claim 7, wherein the spiro ring system comprises two rings each containing a heteroatom. The compound of claim 7, wherein the spiro ring system contains a ring without heteroatoms. The compound of claim 1, wherein R ¹ is a heteroaryl group, wherein the heteroaryl group is substituted with one or more R ² or LR ² as appropriate. The compound of claim 10, wherein the heteroaryl group is a bicyclic or tricyclic ring system containing a non-aromatic ring. The compound of claim 11, wherein the bicyclic or tricyclic ring system is 5,6,7,8-tetrahydro-[1,2,4]triazolopyridine

Base, 5,6,7,8-tetrahydroimidazopyridine

Group, 2,4,5,6-tetrahydropyrrolopyrazolyl, 1,2,3,4-tetrahydrobenzo[4,5]imidazopyrazole

Or 4,5,6,7-tetrahydropyrazolopyridine

base. The compound of claim 3, wherein R ⁷ is hydrogen. The compound of claim 1, wherein R ¹ is hydrogen. The compound of claim 1, wherein R ¹ is a hydroxyl group. The compound of claim 1, wherein R ¹ is -N(R ⁶ ) ₂ . The compound of claim 1, wherein R ¹ is -NR ⁶ C(O)R ⁶ . The compound of claim 1, wherein R ¹ is -C(O)N(R ⁶ ) ₂ . The compound of claim 1, wherein R ¹ is a cycloalkyl substituted with one or more R ^{2 as appropriate.} The compound of claim 19, wherein the cycloalkyl group is cyclobutyl, cyclopentyl or cyclohexyl, each of which is ^{substituted with one or more R 2} as appropriate. The compound of claim 20, wherein the cyclobutyl, cyclopentyl or the cyclohexyl group is substituted with one R ² , wherein R ² is C1-C3 alkyl, alkoxy, halogen, hydroxy or -N(R ⁶ ) ₂ . The compound of claim 1, wherein R ¹ is -Q-heterocyclyl substituted with one or more R ^{2 as appropriate.} Such as the compound of claim 22, wherein Q is a bond, and the heterocyclic group is

Linyl, piperidinyl, piperidine

Base, N-methylpiper

Piperidine

-2-ketone, 1-methyl-piperidine

-2-one, diazepanyl, 6,6-difluoro-1,4-diazepan-1-yl or 4-methylsulfide

1,1-dioxide. The compound of claim 22, wherein Q is a bond, and the heterocyclic group is pyrrolidinyl or tetrahydropiperanyl, each of which is ^{substituted with one or more R 2} as appropriate. The compound of claim 24, wherein the pyrrolidinyl or tetrahydropiperanyl group is substituted with one R ² , wherein R ² is C1-C3 alkyl, alkoxy, hydroxy or -N(R ⁶ ) ₂ . Such as the compound of claim 23, wherein Q is a bond, and the heterocyclic group is optionally substituted ^{by one or more R 2}

base. Such as the compound of claim 26, wherein the piperidine

The group is substituted with one R ² , wherein R ² is heteroaryl, -C(O)cycloalkyl or -C(O)heterocyclyl, wherein the heteroaryl, or the -C(O)cycloalkyl or The cycloalkyl or heterocyclyl moieties of -C(O) heterocyclyl are each optionally substituted ^{with one or more R 11.} The compound of claim 27, wherein R ² is -C(O) cycloalkyl, wherein the cycloalkyl is a ^{cyclopropyl substituted with one R 11} , wherein R ¹¹ is a C1-C3 alkyl. The compound of claim 27, wherein R ² is -C(O) cycloalkyl, wherein the cycloalkyl is a ^{cyclopropyl substituted with one R 11} , wherein R ¹¹ is a haloalkyl. The compound of claim 27, wherein R ² is -C(O) heterocyclic group, wherein the heterocyclic group is oxetanyl, tetrahydrofuranyl or tetrahydropyranyl. The compound of claim 22, wherein Q is a bond, and the heterocyclic group is a bicyclic heterocyclic group. The compound of claim 31, wherein the bicyclic heterocyclic group is diazabicyclo[3.2.0]heptan-2-yl, (1R,5R)-2,6-diazabicyclo[3.2.0]hept- 2-yl, diazabicyclo[3.2.0]hept-6-yl, (1R,5R)-2,6-diazabicyclo[3.2.0]hept-6-yl, 6,7-dihydro Pyrazolo[1,5-a]pyridine

-5(4H)-base, 5,6-dihydroimidazo[1,5-a]pyridine

-7(8H)-yl, 1,3-dimethyl-5,6-dihydroimidazo[1,5-a]pyridine

-7(8H)-yl or (R)-2-methylhexahydropyrrolo[1,2-a]pyridine

-6(2H)-ketone. The compound of claim 22, wherein Q is O, and the heterocyclic group is azetidinyl, tetrahydrofuranyl, pyrrolidinyl or piperidinyl. The compound of claim 1, wherein R ¹ is an aryl group substituted with one or more R ^{2 as appropriate.} The compound of claim 34, wherein the aryl group is a phenyl group substituted ^{with one or more R 2 as the case may be.} The compound according to item 35 of the request, wherein the phenyl group substituted with one R ^2, wherein R ² is C1-C3 alkyl, alkoxy, hydroxy, or -N (R ⁶⁾ _2. The compound of claim 1, wherein R ¹ is a heteroaryl substituted with one or more R ^{2 as appropriate.} The compound of claim 37, wherein the heteroaryl group is a pyrazolyl group substituted ^{with one or more R 2 as appropriate.} The compound of claim 38, wherein the pyrazolyl is substituted with one R ² , wherein R ² is C1-C3 alkyl, alkoxy, hydroxy or -N(R ⁶ ) ₂ . The compound of claim 1, wherein R ⁷ is a cyano group or an alkoxy group. The compound of claim 40, wherein R ⁷ is an alkoxy group, and the alkoxy group is a methoxy group. The compound of claim 41, wherein R ¹ is an alkoxy group. The compound of claim 42, wherein the alkoxy group is a methoxy group. The compound according to any one of claims 1 to 44, wherein Y is a heteroaryl group. The compound of claim 44, wherein the heteroaryl group is thienyl group. The compound according to any one of claims 1 to 45, wherein Y is a bond. The compound according to any one of claims 44 to 46, wherein R ⁴ is an aryl group or a heteroaryl group, each of which is optionally substituted ^{with one or more R 5 groups.} The compound of claim 47, wherein R ⁴ is an aryl group substituted with one or more R ^{5 as appropriate.} The compound of claim 48, wherein the aryl group is a phenyl group substituted ^{with one or more R 5 as appropriate.} The compound according to item 49 of the request, wherein the phenyl group substituted with one R ^5, wherein R ⁵ is C1-C4 alkyl, haloalkyl or -LN (R ⁶⁾ _2. The compound of claim 50, wherein R ⁵ is -LN(R ⁶ ) ₂ , wherein L is methylene, and one R ⁶ is hydrogen and the second R ⁶ is C1-C3 alkyl. The compound of claim 51, wherein the second R ⁶ is methyl. The compound of claim 52, wherein R ⁵ is -LN(R ⁶ ) ₂ , wherein L is methylene and each R ⁶ is C1-C3 alkyl. The compound of claim 53, wherein each C1-C3 alkyl group is a methyl group. The compound of claim 49, wherein the phenyl group is ^{substituted with two R 5} , wherein one R ⁵ is a C1-C3 alkyl group and the second R ⁵ is a haloalkyl group. The compound of claim 55, wherein the C1-C3 alkyl group is a methyl group, and the haloalkyl group is a trifluoromethyl group. The compound of claim 49, wherein the phenyl group is ^{substituted with two R 5} , wherein one R ⁵ is a C1-C3 alkyl group and the second R ⁵ is -LN(R ⁶ ) ₂ . The compound of claim 51, wherein the C1-C3 alkyl group is a methyl group, L is a methylene group, and each R ⁶ is a C1-C3 alkyl group. The compound according to any one of claims 1 to 58, wherein R ³ is a C1-C6 alkyl group. The compound of claim 59, wherein the C1-C6 alkyl group is methyl, ethyl or isopropyl. The compound according to any one of claims 1 to 58, wherein R ³ is a haloalkyl group. The compound according to any one of claims 1 to 58, wherein R ³ is a cycloalkyl group substituted with a halogen amino group, a hydroxyl group, or an alkoxy group as appropriate. The compound of claim 62, wherein the cycloalkyl group is cyclopropyl. The compound according to any one of claims 1 to 58, wherein R ³ is an alkoxy group. The compound according to any one of claims 1 to 58, wherein R ³ is -N(R ¹⁰ ) ₂ . The compound according to any one of claims 1 to 58, wherein R ³ is hydrogen. The compound according to any one of claims 1 to 66, wherein R ⁸ is a C1-C2 alkyl group. The compound of claim 67, wherein the C1-C2 alkyl group is a methyl group. The compound according to any one of claims 1 to 68, wherein R ⁸ is a halo C1-C2 alkyl group. The compound of claim 69, wherein the halo C1-C2 alkyl group is fluoromethyl, difluoromethyl or trifluoromethyl. Such as the compound of claim 1, wherein the compound is selected from the group consisting of:

, And its pharmaceutically acceptable salts. A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) as claimed in any one of claims 1 to 71 or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient Agent. A method for inhibiting the activity of SOS1 in a cell, which comprises making a cell in which the activity of SOS1 needs to be inhibited and an effective amount of a compound of formula (I) as claimed in any one of claims 1 to 71 or a pharmaceutically acceptable salt thereof or Solvate, or contact with the pharmaceutical composition of claim 72. The method of claim 73, wherein the cell has an activating mutation in a gene of a RAS family member. The method of claim 73, wherein the cell has an activating mutation of the SOS1 gene. The method of claim 73, wherein the cell has an activating mutation in the NF-1 or NF-2 gene. A method for treating cancer, the method comprising administering to a patient suffering from cancer a therapeutically effective amount of any one of claims 1 to 64 alone or in combination with a pharmaceutically acceptable carrier, excipient or diluent The compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutically acceptable salt or solvate thereof. The method of claim 77, wherein the therapeutically effective amount of the compound is between about 0.01 to 300 mg/kg per day. The method of claim 78, wherein the therapeutically effective amount of the compound is between about 0.1 to 100 mg/kg per day. The method according to any one of claims 77 to 79, wherein the cancer is selected from the group consisting of: heart: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyomas, fibromas, Lipoma and teratoma; lung: bronchial carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchial) carcinoma, bronchial adenoma, sarcoma, lymphoma, cartilage malocclusion Tumor, mesothelioma; gastrointestinal tract: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, pancreatic height Glucagonoma, gastrinoma, carcinoid, vasoactive intestinal peptide tumor (vipoma), small intestine (adenocarcinoma, lymphoma, carcinoid, Kaposi's sarcoma), leiomyoma, hemangioma, Lipoma, neurofibroma, fibroma), large intestine (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); urogenital tract: kidney (adenocarcinoma, Wilm’s tumor (Wilm's tumor (wilms tumor), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (sperm cell tumor, teratoma, Embryonic carcinoma, teratoma epithelioma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenomatoid tumor, lipoma); liver: liver cancer (hepatocellular carcinoma), cholangiocarcinoma, hepatocellular carcinoma Cell tumor, angiosarcoma, hepatocellular adenoma, hemangioma; biliary tract: gallbladder cancer, ampullary carcinoma, cholangiocarcinoma; bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma (Ewing's sarcoma), malignant lymphoma (reticular cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochondroma (osteochondral exostosis), benign chondroma, chondroblastoma Tumor, chondromycinoma, osteoid osteoma, and giant cell tumor; nervous system: skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges (meningiomas, meningiosarcoma, glioma) Disease), brain (astrocytoma, medulloblastoma, glioma, ependymoma, blastoma (pineal tumor), glioblastoma multiforme, oligodendritic glioma , Schwannoma, retinoblastoma, congenital tumors), spinal cord (neurofibromas, meningioma, glioma, sarcoma); Gynecology: uterus (endometrial carcinoma (serous cystadenocarcinoma, mucinous cyst glands) Cancer, unclassified cancer), granulosa-sheath cell tumor, Sertoli-Leydig cell tumor, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, epithelial Internal cancer, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonic rhabdomyosarcoma), fallopian tube (carcinoma); Hematology: blood (myelogenous leukemia (acute and Chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disease Disease, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma); skin: malignant melanoma, basal cell carcinoma, Squamous cell carcinoma, Kaposi's sarcoma, mole dysplasia, lipoma, hemangioma, dermatofibroma, keloid, psoriasis; and adrenal gland: neuroblastoma. The method according to any one of claims 77 to 80, wherein the cancer is a cancer related to the Ras family. The method of claim 81, wherein the cancer related to the Ras family is KRas, HRas, or NRas G12C-related cancer; KRas, Hras, or NRas G12D-related cancer; KRas, HRas, or Nras G12S-related cancer; KRas, HRas, or NRas G12A-related cancers; KRas, HRas, or NRas G13D-related cancers; KRas, HRas, or NRas G13C-related cancers; KRas, HRas, or Nras Q61X-related cancers; KRas, HRas, or Nras A146T-related cancers; KRas, Hras, or NRas A146V-related cancer; or KRas, HRas, or NRas A146P-related cancer. The method of claim 82, wherein the cancer related to the Ras family is a cancer related to KRas G12C. The method of claim 83, wherein the cancer related to the Ras family is non-small cell lung cancer or pancreatic cancer. The method according to any one of claims 77 to 803, wherein the cancer is SOS1-related cancer. The method of claim 85, wherein the SOS1 related cancer is SOS1 N233S related cancer or SOS1 N233Y related cancer. The method according to any one of claims 85 or 86, wherein the SOS1-related cancer is lung adenocarcinoma, embryonic rhabdomyosarcoma, testicular seteri cell tumor, or skin granulosa cell tumor. The method according to any one of claims 77 to 80, wherein the cancer is an NF-1/NF-2 related cancer.